Neuropathic Pain in Multiple Sclerosis

Wojciech Pietkiewicz

The Walton Centre

Objectives • To be able to understand what chronic pain is • To recognise how important it is for patients with MS• To grasp the principles of treatment

Definition • Chronic pain syndrome (CPS) is a poorly defined condition and one of the most

confusing ones• 6 months 3 months are used as the minimum time criterion.• Any pain that persists longer than the reasonably expected healing time for the

involved tissues should be considered chronic pain.• Neuropathic pain is defined by the International Association for the Study of Pain

(IASP) as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic. • Described as a burning, sharp, stabbing or shooting, or 'like an electric shock‘.• Central neuropathic pain is pain caused by a lesion or disease of the central

somatosensory nervous system.

Taxonomy • Hyperalgesia- Increased pain from a stimulus that normally provokes

pain.• Hyperesthesia- Increased sensitivity to stimulation, excluding the

special senses.• Hyperpathia- A painful syndrome characterized by an abnormally

painful reaction to a stimulus, especially repetitive.• Allodynia- Pain due to a stimulus that does not normally provoke pain.• Paresthesia- An abnormal sensation, whether spontaneous or evoked.

Facts• Clinically significant pain is experienced by as many as 65% of patients

with MS at some time during the disease course. Estimates of prevalence range from 40 to 85%.• In the majority of these of patients pain is persistent and poorly

controlled.• Pain is one of the most disabling features of MS.• Pain in MS is underrecognized and often inadequately treated.

Facts • Pain can develop at any time during the course of the disease and 20% of

MS patients experience pain at disease onset.• In the NARCOMS (North American Research Committee on Multiple

Sclerosis) project:- > 80% reported experiencing one or more forms of neuropathic

pain or uncomfortable paresthesias.- 58% reported actively ‘aching leg pain’.

- 47% indicated that it was at least moderate in severity, meaning that it altered life-style or required medication.

Background facts• 40% of population experience daily pain• 50% of population see their GP for pain being main complaint

Why do we need pain at all?• Pain is essential for survival and is one of the most useful evolutionary

contraptions• Intuitive understanding especially from the patient’s perspective is

that of acute pain.

How this can free you from pain:

Ethiology • CPS might be a learned behavioral syndrome that begins with a

noxious stimulus that causes pain. From that point of view chronic pain should be regarded as a functional disorder.• External reinforcers include such factors as attention from family

members and friends, socialization with the physician, medications, compensation, and time off from work• Patients with several psychological syndromes (eg, major depression,

somatization disorder, hypochondriasis, conversion disorder) are prone to developing CPS

• Primarily pain is a result of tissue or sensory pathway damage. • The nerve fibers themselves may be damaged, dysfunctional, or

injured. These damaged nerve fibers send incorrect signals to other brain centers. The impact of nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury.• The CNS modification, modulation and adaptation for pain is the key

problem

How does it start…

A very short (too common) story • Mr P tries to hammer a nail and hits his left index finger

• The tissue is abruptly damaged and Mr P’s nociceptors are stimulated by number of chemicals immediately released to the surrounding area (potassium ions, bradykinins, prostaglandins, serotonin, substance P, histamine). • This process is called transduction

• Before Mr P realises of the number of substances involved the first warning signal will be sent through large diameter, myelinated very fast fibres called A-delta. They will send signal to the dorsal horn in the spinal cord. • This signal then will travel from the spinal cord to the brain stem• Following this the unfortunate information will go through

connections between the thalamus, cortex -higher levels of the brain• As a result Mr P will regretfully feel very sharp, stinging, well localised

pain in his index finger.

• This is only the beginning of unpleasant sensation. • More or less at the same time slow, small caliber, unmyelinated fibres

called C fibres provide the same information that goes the same path but slowly. • There is a second long delay and to add to the previous sensation Mr

P gets diffuse, dull, burning and aching pain (called second pain)• The phase in which pain is transmitted to the brain is called transmission.

• The brain does not have any especially dedicated pain centre, so when impulse arrives in the thalamus it is directed to multiple areas in the brain where it is processed.• This causes quite a multimodal reaction known to every one. This is

called perception.

What happens next?• Mr P automatically removes his hand immediately looks at his finger. He tries to asses the

potential damage looking at it. This is due to involvement of the reticular system. This is responsible for the autonomic and motor response to pain and for warning the individual to do something. He feels a bit faint and hot.

• Mr P realises it is his finger that got hurt. Mr P realises the last time it happened to other two fingers. He involves his somatosensory cortex: This is responsible for the perception and interpretation of sensation. It identifies the intensity, type and location of the pain and relates the sensation to past experiences, memory and cognitive activities. It identifies the nature of the stimulus before it triggers a response, for example, where the pain is, how strong it is and what it feels like.

• Mr P utters a few swear words although it is not his usual habit. He involves his limbic system: This is responsible for the emotional and behavioural responses to pain for example, attention, mood, and motivation, and also with processing pain and past experiences of pain.

Modulation• After initial few minutes pain becomes less intense and there are moments

it is almost not there. It comes and goes but it is better over next few days. • Modulation may work both ways. It involves changing the transmission of

pain impulses in the spinal cord. The pathways involved in the modulation of pain are called descending modulatory pain pathways (DMPP). They can either increase in the transmission of pain impulses (excitatory) or a decrease the transmission (inhibition).• In this case Mr P’s modulatory pathways release inhibitory chemicals:

endogenous opioids, (such called enkephalins and endorphins), serotonin (5-HT), norepinephirine (noradrenalin), gamma-aminobutyric acid (GABA), neurotensin, acetylcholine, oxytocin.

Further life of Mr P- option 1• After two weeks pain subsides completely and the bruise in the left

index finger almost disappears. Mr P slowly forgets about the pain. He decides the job can be done by someone else although he is happy to instruct. • He will remember that handling hammer may pose a risk. • Mr P has no further problems

Further life of Mr P- option 2• Mr P has annoying pain that he wants to go as quickly as possible. • He takes a few tablets of paracetamol but discovers that they do not

help very much-just taking the edge of it. • Mr P impatiently waits for recovery as he has a lot of things to do.

Wakes up in the morning takes some paracetamol and hopes he might wake up next day with no problem whatsoever.

Further life of Mr P- option 2• After one month however the pain is not gone and Mr P is increasingly frustrated.

What is more he noticed that pain is occasionally more intense and that is why he adopted a habit of drawing his attention to it every few minutes to check if it is still there. The bruise is long gone and there is nothing else that could indicate there is something wrong. Mr P’s spinal cord facilitates impulsation heading towards the brain through the mechanism called ‘wind-up’, also referred to as hypersensitivity or hyperexcitability. The dorsal horn neurones transmit progressively increasing numbers of pain impulses as it appears there is still some damage that requires protection of the finger.• The pain starts affecting the whole hand. It is enough he touches his hand and he has

unpleasant burning sensation. He tries to avoid doing things with that hand and is cautious not to touch it. The process is called peripheral sensitisation. At this point Mr P goes to see his GP

• The GP prescribes various medications which do not help so Mr P is increasingly worried. He has X-ray of his hand and nothing useful is discovered. He has nerve conduction study but contrary to what he felt it would show-there is no damage to be seen in any nerves. • Mr P starts googling his symptoms and discovers number of medical

conditions that could be responsible for intractable pain. Over the next months he will see number of doctors who will be consistently providing no explanation to his symptoms.

• One day he was terrified to see his hand is getting weaker and that goes much beyond the painful finger. He is dropping things, lost a lot of dexterity and his hand does not listen to him. It persistently wakes him up. Due to the mechanism of brain plasticity his brain tries to adjust to new conditions and assumes the pain was there long enough not to subside ever. It switches to ‘chronic mode’ and creates the whole functional area that will serve to generate symptoms which will force Mr P to protect his hand from damaging it more. The process is called central sensitisation.• He throws the hammer away. He looses interest in housework.• He becomes irritable, moody or frankly depressed. He looses trust in his doctor

and all medical profession. He has problems being off work for a long time. He feels tired and generally ill. He thinks of cutting off his finger or the whole hand.

• Chronic pain is reflexion of CNS plasticity and adjustment of neural pathways that facilitate feeling of pain probably in the mechanism of long term protection.• Do not forget there is a lot of functionality (psychosomatisation) in

most of patients with chronic pain.

Homunculus: reflects cortical sensory representation of particular anatomical areas.

“Painculus”. In this case pain of the left upper limb

Why patients with MS have so much pain?

• Similar to vertigo pain may be output of confusing information that gets to the brain. Impulsation that is spread over time is not processed in a normal way and gives as a result unpleasant sensation. In this case it is central pain. • The mechanism of this pain becoming chronic is exactly the same as in any other

condition. • Chronicity of the basic condition like in MS will translate into likelihood of

developing chronic pain.• Cognitive problems and difficulty coping will add to the way patients perceive

their pain.• Psychosomatisation will have significant impact. • The main driver for establishing chronic pain is fear.

Facts:• Presence of pain is independent of Expanded Disability Status Scale

(EDSS).• In most studies pain is associated with depression and, especially,

with anxiety.• Women have a statistically higher prevalence of pain.• Chances of having pain after the age of is 50 reduced.• There is strong inverse association between relapses and pain.

Facts• Individuals living with MS who report high levels of chronic pain and

depressive symptoms may benefit from treatment approaches that can address sleep, fatigue, and anxiety.• Pain is subjective and cannot be measured.• Pain is invisible. • Pain cannot be shown on tests.• Chronic pain is not curable (but may be made better).• Patients need to know the goal is not to take the pain away.

Measuring pain• Visual analogue scale:No pain-----------------------------------------------worst pain• Numerical rating scale:0------------------------------------------------------10• Categorical scale:None, mild, moderate, severe

Treatment • Most important part of treatment should be understanding and

establishing the goals.• The goals need to be reasonable. • The patient who does not understand what the chronic pain is will be

unlikely to get any response from treatment of any sort.• Management of pain is highly complex. There are many ways of

approaching the problem and they should be tailored individually.• There will be side effects from all medications used and particularly

for MS they will not be compatible with other common symptoms.

Treatment options are complex• Pharmacology• Psychology• Anaesthesiology• Neurostimulation• Surgery • Lifestyle • Rehabilitation

Predictors of poor outcome and pain related disability• Avoidance behavior• Negative belief that pain is harmful or disabling• Excessive focusing on pain• Expectation on passive pain management

Pharmacology • Patients would intuitively prefer having tablets for pain as it is a plain,

straightforward way of delivering treatment. It is easy to understand and in patient’s mind it will translate to traditional well known treatment. • This applies well however only to acute pain killers.

Chronic pain killers• They belong to other groups and are usually those primarily used for

other disorders mainly depression and epilepsy.• The mechanism of action is less than understood. The drugs change the

way brain processes pain up or down regulating number of receptors. • It takes a long time to initiate those changes so the drugs start working

within a few weeks from the time proper dose is reached. • The patient needs to know both things or they will be noncompliant. • The drugs do not take the pain away. Only decrease the way it is

processed

Non opioid simple analgesia • Paracetamol. Commonly used. Poor antiinflammatory effect. Well

tolerated. May be used in pregnancy. • Nonsteroids: inhibit cyclooxygenase, reduce prostaglandin level,

mainly used in acute pain. Some antiinflammatory action.

Tricyclic antidepressants • TCAs were the first therapy that proved to be effective for

neuropathic pain in a randomized, placebo-controlled trials• TCAs increase the activity of norepinephrine and serotonin by

blocking their reuptake. • They also modulate sodium channels peripherally• They act as weak NMDA antagonists

Common side-effects• Dry mouth• Weight gain• Sedation• Constipation• Sexual dysfunction• ArrhythmiasIt is rarely that specifically patients with MS would be happy with those

• Amitryptyline is the primary drug. The minimum doses used for pain in clinical trials are 50mgs upwards. Rarely tolerated at those levels. • Nortryptyline at the same dose is deprived of most of sedative

properties. For management of central pain it shows the highest gain. • Nortryptyline gain scoring: 84% gain, amitriptyline (probably the most

used in clinical practice) provides on average: 41% Net Gain.• Other TACs can be used as well although their effectiveness in

metaanalyses shows as follows:• amitriptyline > clomipramine > = desipramine > = imipramine > = doxepin.

SNRIs (Serotonin–norepinephrine reuptake inhibitor)

• Duloxetine shows some effectiveness at minimum 60mg with fewer side effects but evidence is not as strong.• Primarily developed for treatment of depression and anxiety.

Antiepilepstics • Gabapentin• Ill-defined effects on GABA metabolism.• It has fairly few side effects (drowsiness, dizziness, gastrointestinal

symptoms and mild peripheral edema).• No body metabolism (no interactions).• Often good effect on spasticity. • The doses are 900mg to start with going to a few thousand mg.

Pregabaline • Similar to gabapentin but has more affinity to voltage-gated

calcium channels.• The onset of action is shorter.• Similar side effects to gabapentin but often patients can tolerate either.• Has antidepressant and mood stabilising properties. • May help with sleep. Induces a significant increase of REM sleep and a

decrease of stage 2 NREM sleep (as opposed to Amitriptyline which reduces REM). In other words Pregabaline works for more refreshing part of sleep. • Given twice a day and in case of tiredness may be dosed assymetrically.

Carbamazepine • Sodium channel blocker. • Practically used for trigeminal neuralgia (postherpetic neuralgia). • May be useful for other paroxysmal disorders• Oxcarbazepine may be used with fewer side effects and better

tolerance.

Lamotrigine• Sodium channel blocker, mainly used for lancinating, burning type of

pain. • Large number of interactions.• Effective doses 200 to 600mg daily.• High frequency of rash and slow titration needed.

Valproate• Efficacious in diabetic neuropathy.• Has not been studied in MS.• Valproate is an excellent mood stabilizer, and can be considered for

the therapy of mood disorders together with paresthesias.• Causes significant weight gain, alopecia, sedation.• Has significant drug interactions. • The usual dose for neuropathic pain is 1000–1500 mg

Topiramate and zonisamide• Complicated mechanism of action.• It has been shown to modulate the nociceptive reflexes in MS patients with

paroxysmal symptoms.• May be used to treat refractory pain in MS.• The usual daily dose to treat pain is 100–200 mg. • Causes significant weight loss (in 10–20% of patients), word-finding difficulties, and

kidney stones.• Can cause marked concentration problems, depression including suicidal ideations. • Very good indication for concomitant migraine.

Baclofen• Stimulating GABA receptors. • Mainly used in MS to treat trigeminal neuralgia. • It is also used as a first-line antispasticity drug. • The typical effective dose for the treatment of spasticity is 60–100 mg

daily. • Adverse effects include muscle weakness, drowsiness, dry mouth,

confusion and lightheadedness.

Clonazepam• Very strong medication for muscle spasms especially in conjunction

with sodium channel blockers.• Major problem is sedation/fatigue (works up to 36 hours) and

depression.• Highly addictive.• May be used in patients with intractable spasms and problems with

sleep.

Levetiracetam• Very anecdotal reports but in general poor evidence.• Unknown mode of action (potassium channels?).• No known interactions.• Well tolerated and fast titration.• May cause mood issues.

NMDA antagonists• Glutamate is a major excitatory neurotransmitter of the

CNS associated with chronic pain and opioid tolerance,dependence, and addiction.

• It plays an important role in central sensitizationand “wind-up” leading to allodynia and hyperalgesia.

• NMDA antagonists reduce spontaneous pain and hyperalgesia,acute postop pain, and chronic neuropathic pain.

• Ketamine is used in sub-anaesthetic doses. Has small therapeutic window and is potentially toxic.• Drugs of weaker affinity to NMDA receptors: dextromethorphan, amantadine, memantine and

magnesium.• High gene polymorphism in metabolising drugs with very variable results for pain and side effects.

Opioids • Work through central and peripheral opioid receptors.• The use of opioids in the management of neuropathic pain remains

controversial.• Mainly beneficial in poorly localized burning pain.• Studies in MS showed some benefit only in high doses.• Opioids are no better than any other type of analgesia!• Codeine has very poor abilities as a chronic pain killer.

• Oxycodone (target initial 10mg bd)• Fentanyl patch (one patch per 3 days). It is the most expensive pain medication in

MS.• Morphine-primary drug (at initial dose of 15mg bd) is short acting and may be used

for break-through pain.• Common side-effects of opioids include constipation, sedation and nausea, cognitive

impairment.• Physical dependence on opioids develops in most patients, and may lead to

withdrawal symptoms with sudden discontinuation or with a rapid reduction in dose.

Cannabinoids • Some reports have suggested that cannabis may be beneficial in controlling

symptoms such as spasticity, pain, tremor and bladder dysfunction (self medication of cannabis). • Interestingly cannabis preparations claim to improve pain and spasticity in MS

patients; however, no objective change in spasticity was seen on any studies. • Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray

(Sativex) showed very equivocal results for pain management (the drug is not significantly better than placebo).

Polyneuropathy

Central pain

Other treatments• Lignocaine patch. • Used fro well localised pain, poor evidence for MS

• Capsaicin cream/patch• No evidence for MS (potentially useful)

• Nerve blocks• Used in well localised pain, cheap and fast acting, but no evidence in MS

• Baclofen pump (has effect on neuropathic pain to some extent although it is used for spasticity)

Neurostimualtion• TENS• Mixed results but some consistency in usefulness in MS. Cheap, non-

pharmacological alternative

• Accupuncture• No hard evidence

• Lateral-lead spinal cord stimulation

• There are no proper randomised clinical trials for chronic pain in multiple sclerosis!• The only exception are experimental treatments of cannabinoids.

Which drug should be considered?• Good evidence should have priority. • Practically trial of one medication may end up with trying all available on the

market going form best evidence to almost experimental• Combination of TCAs and antiepileptic painkillers will work better (at the

cost of side effects)• The drug chosen should pair other desired effect (like use of topiramate in a

patient with migraine)• Side effects will decide about the first line use rather than pain killing effect!• Final decision with regards to treatment and the choice of tablets belongs

to the patient

What does NICE say?• Offer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial

treatment for neuropathic pain (except trigeminal neuralgia).• If the initial treatment is not effective or is not tolerated, offer one of the

remaining 3 drugs, and consider switching again if the second and third drugs tried are also not effective or not tolerated.• Consider tramadol only if acute rescue therapy is needed.• Consider capsaicin cream for people with localised neuropathic pain who

wish to avoid, or who cannot tolerate, oral treatments.• Do not use (unless in specialist setting): cannabis sativa extract, capsaicin

patch, lacosamide, lamotrigine, levetiracetam, morphine, oxcarbazepine, topiramate, venlafaxine.

Audit in management of pain in MS (The Walton Centre and community)• 1 Identification of the problem (the clinician needs to be aware that the problem

exists) [NICE 1.7.11.1]

• 2 Assessment of the problem (does the pain affect the patient and to what degree?)

• 3 Offering proper management including pharmacology (incorporating chronic/acute painkillers and indications versus side effect profile) [NICE 1.7.11.8]

• 4 reassessment if the patient with regards to benefit and side effects [NICE 1.1.9]

• 5 Adjusting the treatment appropriately.

Audit in management of pain in MS (The Walton Centre and community)•Only 66% of patients were assessed for pain and of those 33% reassessed. Pain was properly controlled in 25% of patients. •Opioids were used first line in 31% of patients. •The average dose of Amitriptyline used was 17.5mg, Gabapentin 1160 and Pregabaline 430/day.

What not to do• Prescribing acute pain killers for chronic pain• Prescribing opioids first line • Prescribing sub-therapeutic doses (the most common problem seen)• Prescribing multiple treatments in medium doses• Prescribing drugs for not sufficient time• Failing to inform the patient about the delay in response• Failing to ask if treatment is necessary• Failing to ask if treatment is needed

Psychology intervention

• Cognitive behavioural therapy• Biofeedback• Counselling • Treatment of depression• Coping strategies• Pain management programms

Rehabilitation

• Physical therapy• Occupational therapy• Cryotherapy • Use of assistive devices• Use of prostheses• Anaesthesia• Surgery • Adjusting lifestyle

Summary • Understanding chronic pain is the key to treatment.• Patients need to know clearly what chronic pain is and what the goals

of treatment are.• Chronic pain is a style of life leading to all aspects of illness and

sparing behaviours (fatigue, weakness, imbalance, avoidance of social contacts, decreased mentation).• There is no cure for chronic pain and good coping strategy with

bearable level of pain is the target.• Acceptable targeted quality of life is the only reasonable aim.

Thank you