1. Neuropathic pain: from pathophysiology to treatment
Andrei Danilov
Department of Neurology
Sechenov Medical University,
Moscow, Russia 1

2. What is pain ? How to treat pain ?3

3. Note to speaker: this is the first slide in the sequence illustrating co-existing pain.
Over the next 3 slides, a typical example of co-existing pain will be demonstrated using low back pain and associated lumbar radiculopathy caused by a herniated disc. These slides will show:
a patient image of low back pain caused by a herniated disc
a close-up diagram of the area of pain
an animated build showing the nervous system involvement in the pain sensation. 4

4. for the adequate treatment ?
What is important
for the adequate treatment ? 5

5. Clinical picture, exams, history Treatment (pharmacotherapy)
Тип боли
Diagnosis
Treatment (pharmacotherapy) 6

6. Differentiated Treatment
Diagnosis
When treating chronic pain condition it is very important to consider not only the diagnosis but also the types and mechanisms of pain
Type of pain
Pain mechanisms
Differentiated Treatment 7

7. Understanding key types of pain
Nociceptive
Neuropathic
Dysfunctional 8

8. Активация ноцицепторов
Nociceptive pain
Pain caused by direct activation of nociceptors by trauma, inflammation, etc
PAIN
Mechanical trauma
Osteoarthritis
Surgery
Descending
modulation
Note to speaker: this slide contains an animation illustrating the flow of activity along a nociceptive afferent fiber following noxious stimulation. Clicking on this slide will cause subsequent components of this animation to run automatically.
Under normal circumstances, impulses are generated in nociceptor terminals only in response to noxious stimuli. The impulses are transmitted to the brain and are perceived as pain.
The ascending input is modulated by the descending control mechanisms.
Активация ноцицепторов 9

9. Example of nociceptive pain: osteoarthritis
Inflammation
Note to speaker: this slide contains an animated build to represent the involvement of the nervous system in chronic nociceptive pain (osteoarthritis of the knee). Clicking on this slide will cause subsequent components of this build to appear automatically.
In osteoarthritis, chronic pain is caused by activation of local nociceptors by inflammation in the affected joint.
These activated nociceptors send impulses along the peripheral (afferent) nerves to the dorsal roots where they enter the spinal cord to reach the dorsal horn.
Signals ascend from the sensory nerves via various pathways to the brain where they give rise to the experience of pain. Pathways include the brain stem, thalamus, limbic system and other cortical areas, which are all responsible for processing sensation, emotion, stress, and memory.
The brain, in turn, sends signals via descending tracts into the dorsal horn to modulate the incoming (afferent) signals from the painful knee joint, and to evoke a reflex or behavioral response to osteoarthritis pain (e.g. rubbing the painful area and restricting movement), or to inhibit the afferent signal entirely.
The goal of osteoarthritis pain treatment is to relieve inflammatory pain with conventional analgesics (acetaminophen [paracetamol], NSAIDS, COX-2 inhibitors or opioids), while maintaining joint function and mobility.
Activation of joint nociceptors

10. Neuropathic pain
Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system
PAIN
Diabetic polyneuropathy
Postherpetic neuralgia
Spinal injury
Poststroke central pain
Note to speaker: this slide contains an animation illustrating the flow of activity along a nociceptive afferent fiber following noxious stimulation. Clicking on this slide will cause subsequent components of this animation to run automatically.
Under normal circumstances, impulses are generated in nociceptor terminals only in response to noxious stimuli. The impulses are transmitted to the brain and are perceived as pain.
The ascending input is modulated by the descending control mechanisms. 11

11. Example of neuropathic pain: DPN
Note to speaker: this slide contains an animated build to represent the involvement of the nervous system in chronic nociceptive pain (osteoarthritis of the knee). Clicking on this slide will cause subsequent components of this build to appear automatically.
In osteoarthritis, chronic pain is caused by activation of local nociceptors by inflammation in the affected joint.
These activated nociceptors send impulses along the peripheral (afferent) nerves to the dorsal roots where they enter the spinal cord to reach the dorsal horn.
Signals ascend from the sensory nerves via various pathways to the brain where they give rise to the experience of pain. Pathways include the brain stem, thalamus, limbic system and other cortical areas, which are all responsible for processing sensation, emotion, stress, and memory.
The brain, in turn, sends signals via descending tracts into the dorsal horn to modulate the incoming (afferent) signals from the painful knee joint, and to evoke a reflex or behavioral response to osteoarthritis pain (e.g. rubbing the painful area and restricting movement), or to inhibit the afferent signal entirely.
The goal of osteoarthritis pain treatment is to relieve inflammatory pain with conventional analgesics (acetaminophen [paracetamol], NSAIDS, COX-2 inhibitors or opioids), while maintaining joint function and mobility.
Pain is arising as a direct consequence of a lesion of peripheral sensory nerves

12. Dysfunctional pain
Resulting from abnormal CNS functioning in the absence of anatomical causes of persistent pain
PAIN
Fibromyalgia
Tension type headache
Irritable bowel syndrome
Note to speaker: this slide contains an animation illustrating the flow of activity along a nociceptive afferent fiber following noxious stimulation. Clicking on this slide will cause subsequent components of this animation to run automatically.
Under normal circumstances, impulses are generated in nociceptor terminals only in response to noxious stimuli. The impulses are transmitted to the brain and are perceived as pain.
The ascending input is modulated by the descending control mechanisms. 13

13. Example of dysfunctional pain: Fibromyalgia
Not sufficient descending inhibition
and increasing pain facilitation
PAIN
Periheral nonpainful stimuli are percieved as painful
Note to speaker: this slide contains an animation illustrating the flow of activity along a nociceptive afferent fiber following noxious stimulation. Clicking on this slide will cause subsequent components of this animation to run automatically.
Under normal circumstances, impulses are generated in nociceptor terminals only in response to noxious stimuli. The impulses are transmitted to the brain and are perceived as pain.
The ascending input is modulated by the descending control mechanisms.
Clifford J Woolf . Central sensitization: Implications for the diagnosis and
treatment of pain. Pain March ; 152(3 Suppl): S2–15

14. what proportion of your patients suffer from neuropathic pain?
Discussion Question
what proportion of your patients suffer from neuropathic pain?
Speaker’s Notes
Ask the question shown on the slide to participants to stimulate discussion.

15. Neuropathic Pain is Prevalent Across a Range of Different Conditions
5–20% of the General Population May Suffer from Neuropathic Pain
Adapted from: Bouhassira D et al. Pain 2008; 136(3):380-7; de Moraes Vieira EB et al. J Pain Symptom Manage 2012; 44(2):239-51; Elzahaf RA et al. Pain Pract 2013; 13(3): ; Harifi G et al. Pain Med 2013; 14(2):287-92; Ohayon MM, Stingl C. Psychiatr Res 2012; 46(4):444-50; Torrance N et al. J Pain 2006;7(4):281-9; Toth C et al. Pain Med 2009; 10(5):918-29; 16

16. The «3L» Approach to Diagnosis
Listen
Patient verbal descriptors of pain, questions and answers
Locate
Look
Somatosensory Nervous system lesion or disease
Sensory abnormalities in the painful area
1. Freynhagen R, Bennett MI. BMJ 2009; 339:b3002; 2. Bennett MI et al. Pain 2007; 127(3): ; 3. Freynhagen R et al. Pain 2008; 135(1-2):65-74; 4. Freynhagen R et al. Curr Pain Headache Rep 2009; 13(3):

17. Listen to the Patient Description of Pain
Question patients about their pain
Be alert and ask for common verbal descriptors of neuropathic pain
Speaker’s Notes
It is important for the clinician to ask the patient about their pain and listen carefully to the patient’s verbal descriptions of their pain, in addition to assessing the patient’s medical history for important diagnostic clues.
Use of a “cluster of terms” may signal neuropathic pain. The use of one or two typical verbal descriptors is highly suggestive of neuropathic pain, although not pathognomonic.
Screening tools can also be used to help distinguish neuropathic from non-neuropathic pain.
References
Cruccu G et al. EFNS guidelines on neuropathic pain assessment: revised Eur J Neurol 2010; 17(8):
Gilron I et al. Neuropathic pain: a practical guide for the clinician. CMAJ 2006; 175(3):
Haanpää ML et al. Assessment of neuropathic pain in primary care. Am J Med 2009; 122(10 Suppl):S13-21; 4.
1. Haanpää ML et al. Am J Med 2009; 122(10 Suppl):S13-21; 2. Gilron I et al. CMAJ 2006; 175(3):265-75; 3. Cruccu G et al. Eur J Neurol 2010; 17(8):

18. LISTEN : Recognizing Neuropathic Pain characteristics
Burning Tingling Shooting Electric Numbness
shock-like
Be alert for common verbal descriptors of neuropathic pain !
Baron R et al. Lancet Neurol 2010; 9(8):807-19; Gilron I et al. CMAJ 2006; 175(3):

19. LOOK: Sensory Symptoms of Neuropathic Pain
Lesion or disease of the somatosensory nervous system
Positive symptoms
(due to excessive neural activity)
Negative symptoms
(due to deficit of function)
Spontaneous pain
Hypoesthesia
Anesthesia
Allodynia
Hyperalgesia
Hypoalgesia
Dysesthesia
Analgesia
Paresthesia
Sensory abnormalities and pain paradoxically co-exist
Each patient may have a combination of symptoms
that may change over time (even within a single etiology)
Baron R et al. Lancet Neurol 2010; 9(8):807-19; Jensen TS et al. Eur J Pharmacol 2001; 429(1-3):1-11.

20. Look: Simple Bedside Tests
Stroke skin with brush,
cotton or apply acetone
Sharp, burning
superficial pain
ALLODYNIA
Light manual pinprick with
safety pin or sharp stick
Very sharp,
superficial pain
Speaker’s Notes
This slide describes several simple assessments, that can readily be employed in the physician’s office, for allodynia (pain due to a stimulus that does not normally provoke pain) and hyperalgesia (increased pain from a stimulus that normally provokes pain). In each case, the control would be the identical stimulus applied to the unaffected contralateral side.
Mechanical allodynia can be assessed by stroking the skin with a brush, gauze, or cotton. Patients with mechanical allodynia might complain that the brushing of fabric such as a shirt over their skin is painful and that they avoid being touched by others, wear shoes or even socks.
Cold allodynia may be tested by applying acetone to the skin.
Mechanical hyperalgesia can be evaluated by using a safety pin or sharp stick to the skin. Patients with pinprick hyperalgesia may complain of very increased painful sensation with this evoked nociceptive stimuli.
References
Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain 2000; 16(2 Suppl):S12-20.
Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 2003; 102(1-2):1-8.
HYPERALGESIA
Baron R. Clin J Pain 2000; 16(2 Suppl):S12-20; Jensen TS, Baron R. Pain 2003; 102(1-2):1-8.

21. LOCATE the Region of Pain
Body maps allow identification of the nervous system
Radiculopathy
Polyneuropathy
Poststroke pain
Mononeuropathy
n. medianus

22. Diagnosing neuropathic pain
Colloca et al., 2017 26

23. Why it is important to understand the types and mechanisms of pain ?27

24. The pathophysiological mechanisms of pain
are the therapeutic targets for medications
Central
Sensitization
Disinhibition,
Pain Facilitation
Pregabalin
Gabapentin
TCAs
SNRI
NA, 5HT
Ca2+
Muscle Spasm
Tizanidin
Tolperizon
Baclofen
Peripheral
Sensitization α2
Na+
Carbamazepine
Lamotrigine
Lidocaine
GABA
Na+
Inflammation
Infliximab
TNF-alpha
Tanezumab
NGF
NSAIDs
COX-2
Capsaicin
TRPV 28

25. Mechanism-Based Pharmacological Treatment of Neuropathic Pain

26. The mechanisms of neuropathic pain
are the therapeutic targets for medications
Central
Sensitization
Disinhibition,
Pain Facilitation
TCAs
SNRI
Pregabalin
Gabapentin
NA, 5HT
Ca2+
Peripheral
Sensitization
Carbamazepine
Lamotrigine
Lidocaine
Na+
Capsaicin
TRPV 30

27. Peripheral sensitization
Nerve lesion induces hyperactivity due to changes in
sodium channel function
PAIN
After peripheral nerve lesion
Disesthesia
Hyperesthesia
Tingling pain
Spontaneous pain
Nerve lesion
Descending modulation
Ascending input
Note to speaker: this slide contains an animation illustrating the consequences of ectopic discharges from a damaged or diseased nociceptive afferent fiber. Clicking on this slide will cause subsequent components of this animation to run automatically.
The equilibrium between ion channels (e.g. sodium and potassium) in the axonal membrane of damaged or diseased neurons becomes altered.
This may result in hyperexcitability causing impulse ‘over-firing’ – also known as ectopic discharges.
Such ectopic discharges may occur spontaneously or may be evoked by mechanical stimuli (e.g. touch, pressure).
Na+
Na+
Na+
Na+
Na+
Nociceptive afferent fiber
Ectopic discharges 31

28. Lidocaine 5% patch (sodium channel blockers)
Pain is reduced due to the blocking of sodium channels
PAIN
Lidocaine
Nerve lesion
Note to speaker: this slide contains an animation illustrating the consequences of ectopic discharges from a damaged or diseased nociceptive afferent fiber. Clicking on this slide will cause subsequent components of this animation to run automatically.
The equilibrium between ion channels (e.g. sodium and potassium) in the axonal membrane of damaged or diseased neurons becomes altered.
This may result in hyperexcitability causing impulse ‘over-firing’ – also known as ectopic discharges.
Such ectopic discharges may occur spontaneously or may be evoked by mechanical stimuli (e.g. touch, pressure).
Na+
Na+
Na+
Na+
Na+
Nociceptive afferent fiber
Ectopic discharges 32

29. Anticonvulsants (sodium channel blockers)
Pain is reduced due to the blocking of sodium channels
PAIN
Carbamazepine
Lamotrigine
Oxcarbazepine
Topiramate
Descending modulation
Ascending input
Nerve lesion
Note to speaker: this slide contains an animation illustrating the consequences of ectopic discharges from a damaged or diseased nociceptive afferent fiber. Clicking on this slide will cause subsequent components of this animation to run automatically.
The equilibrium between ion channels (e.g. sodium and potassium) in the axonal membrane of damaged or diseased neurons becomes altered.
This may result in hyperexcitability causing impulse ‘over-firing’ – also known as ectopic discharges.
Such ectopic discharges may occur spontaneously or may be evoked by mechanical stimuli (e.g. touch, pressure).
Na+
Na+
Na+
Na+
Na+
Nociceptive afferent fiber
Ectopic discharges 33

30. Capsaicin 8% patch (Qutenza)
Provides pain relief by acting on pain nerves in skin
(initial painful sensation followed by pain relief)
PAIN
Capsaicin
TRPV1
Note to speaker: this slide contains an animation illustrating the consequences of ectopic discharges from a damaged or diseased nociceptive afferent fiber. Clicking on this slide will cause subsequent components of this animation to run automatically.
The equilibrium between ion channels (e.g. sodium and potassium) in the axonal membrane of damaged or diseased neurons becomes altered.
This may result in hyperexcitability causing impulse ‘over-firing’ – also known as ectopic discharges.
Such ectopic discharges may occur spontaneously or may be evoked by mechanical stimuli (e.g. touch, pressure).
Na+
Na+
Na+
Nociceptive afferent fiber
Ectopic discharges 34

31. Qutenza ® - high dose capsaicin 8% patch
Approved FDA for PHN in 2009
Resulted in pain reduction within one week and sustained up to 3 months after a single application
Must be applied in physician office for one hour then removed, premedication of local anesthetic required
SE: redness, itching, pain of application site, transient inc in BP
This slide can be placed immediately after slide 64, which summarizes the recent EFNS guidelines for the treatment of painful polyneuropathy. 35

32. Central sensitization (CS)
CS - is a hyperactivity of sensory neurons in the CNS that leads to enhanced pain
PAIN
Allodynia
Secondary Hyperalgesia
Wind-up
Clifford J Woolf, 2011 36

33. Anticonvulsants (gabapentinoids) Central sensitization
Provide pain relief by binding to  subunit protein of Ca channel and decreasing release of pain mediators (Glu, SP) Са
Central sensitization
Gabapentin
Pregabalin
Ca2+
Therapeutic options for neuropathic pain management could act via different mechanisms.
Therefore, successful neuropathic pain management frequently requires a combined therapeutic regimen. 37

34. Pregabalin Starting dosage 50 or 75 mg twice daily for 3-7 days
Increase slowly up to 600 mg as tolerated
Reduce dosage if impaired renal function
Duration of adequate trial 4 weeks
This slide can be placed immediately after slide 64, which summarizes the recent EFNS guidelines for the treatment of painful polyneuropathy.
N/ Attal, et al 2010, R.H. Dworkin et al. Pain, 2007
R.H. Dworkin et al. / Pain 132 (2007) 237–251

35. Gabapentin Starting dosage 100–300 mg at bedtime
Increase by 100–300 mg three times daily every 1–7 days as tolerated
Maximum dosage 3600 mg daily (1200 mg x 3)
Reduce dosage if impaired renal function
Duration of adequate trial 3–8 weeks for titration plus 2 weeks at maximum dosage
This slide can be placed immediately after slide 64, which summarizes the recent EFNS guidelines for the treatment of painful polyneuropathy.
N/ Attal, et al 2010, R.H. Dworkin et al. Pain, 2007
R.H. Dworkin et al. / Pain 132 (2007) 237–251

36. Nociceptive afferent fiber
Disinhibition
Loss of descending modulation causes exaggerated pain due to an imbalance between ascending and descending signals
Long duration of pain
Generalization of pain
Depression
Insomnia
Low quality of life
Exaggerated
pain perception
Noxious stimuli
Note to speaker: this slide contains an animation to illustrate the consequences of the loss of inhibitory controls following impulses in a nociceptive afferent fiber. Clicking on this slide will cause subsequent components of this animation to run automatically.
Under normal circumstances, the information transferred from the periphery to the brain depends on the balance of ascending (excitatory) and descending (inhibitory) modulation acting on dorsal horn neurons.
Under pathological circumstances, inhibitory controls may be lost or impaired, causing dorsal horn neurons to ‘over-fire’ in response to sensory input, leading to an exaggerated pain response.
Loss of descending modulation
Ascending input
Nociceptive afferent fiber 40

37. Antidepressants
Augment descending noradrenergic and serotoninergic inhibitory pathways
TCAs
- Amitryptiline
SNRIs
- Duloxetine
- Venlafaxine
- Milnacipran NA
5HT
Therapeutic options for neuropathic pain management could act via different mechanisms.
Therefore, successful neuropathic pain management frequently requires a combined therapeutic regimen. 41

38. Descending pain modulatory systems: noradrenergic (NE) and serotoninergic (5HT)
Inhibitory
(pain relief) NE
5HT
Facilitating
(pain increase)
SSRIs
are not used !
Alpha 2
adreonorecepors
5HT1
5HT3

39. TCA - Amitryptiline Start at low dose 10-25 mg at bedtime
Tolerability improved with gradual dose titration:
titrate by 10-25mg daily every 3-7 days to mg/day
Maximum dosage 150 mg daily
Duration of adequate trial 6–8 weeks with at least 2 weeks at maximum tolerated dosage
Adverse Effects (sedation, drowsiness, weight gain, dry mouth)
Analgesic effect is independent of antidepressant effect
This slide can be placed immediately after slide 64, which summarizes the recent EFNS guidelines for the treatment of painful polyneuropathy.
N/ Attal, et al 2010, R.H. Dworkin et al. Pain, 2007

40. SNRI: Duloxetin Starting dosage 30mg once daily
Increase to 60 mg once daily after one week
Maximum dosage 60 mg twice daily
Duration of adequate trial 4 weeks
First line treatment in painful DPN
Analgesic effect is independent of antidepressant effect
This slide can be placed immediately after slide 64, which summarizes the recent EFNS guidelines for the treatment of painful polyneuropathy.
N/ Attal, et al 2010, R.H. Dworkin et al. Pain, 2007
R.H. Dworkin et al. / Pain 132 (2007) 237–251 44

41. Guidelines on pharmacoterapy
of neuropathic pain 45

42. IASP Guidelines: Pharmacological Treatment of NeP
EuCan Regional Medical Team
Slidekit developed for medical communication.
Subject to local approval
IASP Guidelines: Pharmacological Treatment of NeP
1st line
2o amine TCAs (notiptyline, desipramine)
SNRIs (duloxetine, venlafaxine)
A2d ligands (gabapentine, pregabalin)
Topical lidocaine (for localized peripheral NeP)
2nd line
Opioid analgesics*
Tramadol*
Version: February 2011
The recommendations for the pharmacological management of neuropathic pain (NeP) shown on this slide were developed via a consensus meeting conducted under the auspices of the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group with additional support provided by the Neuropathic Pain Institute. Experts reviewed existing treatment guidelines, systematic reviews and meta-analyses, and recently published randomized controlled clinical trials (RCTs). This literature and the authors’ clinical and research experience were discussed during the consensus meeting. Systematic reviews and RCTs published after the meeting were reviewed subsequently. The treatment recommendations made by the expert group have been endorsed by the American Pain Society, the Canadian Pain Society, the Finnish Pain Society, the Latin American Federation of IASP Chapters, and the Mexican Pain Society.
The key talking points for this slide are as follows:
The slide shows “Step 2” of the 4-step approach to the pharmacological management of neuropathic pain. Steps 1, 2 and 4 focus on diagnosis and follow-up.
The expert group felt unable to rank their first-line drug treatment recommendations due to a lack of evidence from head-to-head studies. It therefore recommended drug selection be based on: (1) the potential for adverse outcomes associated with side effects; (2) potential drug interactions; (3) comorbidities that may be relieved by the non-analgesic effects of the medication; (4) cost; (5) potential abuse risk and (6) risk of overdose.
Three medications/medication classes were recommended as 1st-line treatments for patients with NeP, either alone or in combination: the secondary amine tricyclic antidepressants (TCAs) nortriptyline and desipramine, the serotonin noradrenaline reuptake inhibitors (SNRIs) duloxetine and venlafaxine, and the calcium channel α2δ ligands gabapentin and LYRICA (pregabalin).
Topical lidocaine (alone or in combination with other 1st-line agents) was recommended as a 1st-line treatment for patients with localized peripheral NeP.
Opioid analgesics and tramadol, which were generally considered to be 2nd-line therapies, were recommended as 1st-line treatments (alone or in combination with other 1st-line treatments) for patients with acute neuropathic pain, neuropathic cancer pain, or episodic exacerbations of severe pain, and when prompt pain relief during titration of a 1st-line medication to an effective dose was required.
Third-line treatments were considered to include: certain AEDs (carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid), certain antidepressants (bupropion, citalopram, paroxetine), mexiletine, NMDA receptor antagonists, and topical capsaicin.
Specific recommendations for central NeP were: TCAs for CPSP, gabapentin and LYRICA for SCI pain and cannabinoids for NeP associated with multiple sclerosis.
Reference
Dworkin et al. Pain. 2007;132(3):237-5
Initiate therapy of the disease causing neuropathic pain
Initiate symptom treatment with one or more of the following:
Secondary amine TCA (nortriptyline, desipramine)
SNRI (duloxetine, venlafaxine)
Calcium channel α2δ ligand (pregabalin or gabapentin)
Topical lidocaine for localized pain, peripheral NeP, used alone or in combination with one of the other first-line therapies
Opioid analgesics or tramadol, alone or in combination with one of the other first-line therapies ,for acute neuropathic pain, neuropathic cancer pain, or episodic exacerbations of severe pain, and while titrating a first-line therapy to an effective dose
Initiate non-pharmacologic treatment if appropriate
Dworkin et al. Pain. 2007;132(3):237-51
Background Neuropathic Pain Slide Kit: February 2011 Update

43. What about the efficacy of pharmacotherapy of neuropathic pain ?
….Еven first-line treatments are beneficial in less than 50% of patients
…Despite the introduction of new and safer drugs and the publication of several randomized controlled trials supporting evidence-based treatment, many patients still do not obtain sufficient pain relief or do not tolerate adequate doses because of side effects… 47

44. Is phenotyping useful ?
PAIN 159 (2018) 569–575 48

45. From Etiology to Neuropathic Pain Phenotype
Different neuropathic pain phenotypes reflect different mechanisms of pain and help in understanding what medication could be more favorable
von Hehn et al., Neuron February 23; 73(4)
von Hehn et al., Neuron February 23; 73(4)

46. Predicted efficacy of treatment response and rational pharmaceutical treatment
Sensory Thermal Mechanical
loss hyperalgesia hyperalgesia
PAIN 159 (2018) 569–575 50

47. Multimodal treatment of chronic pain is based on biopsychosocial approach
Expectations
Cognitive-behavioral therapy
Physical activity
Pharmacotherapy
Education
Psychological
support
Social support
Meditation
Sleep 52

48. “…If you administer your patients only the drugs and don't give them love – they remain alone, helpless, and continue to suffer, face to face with their problems”
Victor Frankl, In: “Man’s Search for Meaning” 1997