The etiology/anatomy based classification of neuropathic pain syndromes, and some common causing factors. Painful peripheral neuropathies. Phantom limb ...
Current approaches in the treatment of neuropathic and phantom limb pain
Zsuzsanna Helyes M.D., Ph.D., D.Sc., Bálint Botz M.D. Pécs University, School of Medicine, Department of Pharmacology and Pharmacotherapy
Scientific reviewer: János Tajti M.D., Ph.D. Szeged University, School of Medicine, Department of Neurology
English grammar reviewer: Ian O’Sullivan B.Sc.
1. Introduction, etiology, symptomatology 1.1 The definition of neuropathic pain, the classification of neuropathies
Pain is generally divided into three large subgroups: somatic, visceral, and neuropathic forms. Somatic and visceral pain are usually the warning signs of a potentially harmful external factor (e.g touching a hot object) or disease (e.g angina pectoris). In order to develop these painfuls sensations, the excitation of the sensory nerve endings (either in superficial or deeper tissues/organs) is necessary. Therefore these forms of pain are mostly beneficial, as they help to save the structural integrity of the body (e.g. by forcing someone to rest an injured limb). Neuropathic pain on the other hand is a direct consequence of the damage of the nervous system itself, which is according to our current knowledge – practically irreversible. Thus, this form of pain is ”useless”, because it serves no purpose while seriously hindering the patients life quality.
The definition of neuropathic pain is according to the IASP (International Association for the Study of Pain): „Pain caused by a lesion or disease of the somatosensory nervous system.”
The two main aspects in the classification of neuropathic pain: 1. The anatomical localization of the lesion 2. The etiology of the damage By these two considerations most of the patients can be subdivided into four broad categories (Table 1.)
Table 1. The etiology/anatomy based classification of neuropathic pain syndromes, and some common causing factors Painful peripheral neuropathies
Phantom limb pain Traumatic neuroma, nerve injury Postherpetic neuralgia Diabetic mononeuropathy Ischaemic neuropathy Lyme Borelliosis Peripheral nerve tumours Radiotherapy-induced neuropathy Trigeminal/glossopharyngeal neuralgia Vascular
and
other
compresssions Polineuropathies
Metabolic: Diabetic polineuropathy Alcoholic neuropathy Amyloidosis Hypothyreosis Beri-Beri, Pellagra Drug-induced: Antiretroviral drugs Cisplatin, paclitaxel, oxaliplatin Disulfiram Isoniazide Thalidomide
nerve
Vincristin Thiouracil Chloramphenicol Metronidazole etc. Toxin.induced: Arsenic Thallium Acrilamide Dinitrophenol Hereditary: Amyloid neuropathy Fabry-disease Charcot-Marie-Tooth-disease Neoplastic: Paraneoplastic
neuropathy
(carcinomas mostly) Myeloma Infectious/immune: Lyme Borrelliosis HIV Guillain-Barré-syndrome Miscellaneous: „Trench foot” (freeze injury) Idiopathic neuropathies Central pain syndromes
Vascular
neuropathies
(haemorrhagic/ischaemic stroke) Sclerosis multiplex Traumatic injury of the brain or spinal cord Tumours Abscesses Parkinson-disease
Complex
pain
forms
of
mixed CRPS
neuropathic and other origin
(Complex
Regional
Pain
Syndrome I,II) Chronic
low
back
pain
with
radiculopathy
1.2 The epidemiology of neuropathic pain
To determine the exact prevalance of neuropathic pain in the population is difficult, especially in societies with generally low health awareness. According to current estimations neuropathic pain can affect as much as 7-8% of the population in Western-Europe. Most of them are left undiagnosed, but even many of those who are get eventually „lost” in the health system, receiving improper/inadequate treament. A significant percentage of patients does not reach a specialist, and still many try to cure themselves by OTC (over the counter) drugs and other remedies (unsurprisingly without success). The largest group of the patients affected by neuropathic pain are the middle-aged and elderly. Women and people with low SES (socioeconomic status) are also affected more often. The most common cause in developed countries is diabetes mellitus. During the long course of this disease, significant amount of patients develop the typical symptoms of diabetic polineuropathy, even when receiving adequate therapy. Half of those who have suffered spinal cord damage, and 8% of those who had a stroke develop neuropathic symptoms. 10-40% of patients with helpes zoster have also neuropathic symptoms. 10-20 years after the first manifestation of sclerosis multiplex, most of the patients develop chronic neuropathic pain. Among the other common causes trigeminal neuralgia, malignant tumours (either direct invasion of the neural system or the side effect of chemotherapy), operations (thoracotomy, mastectomy, laminectomy) worth mentioning. A significant amount (30-40%) of patients suffering from low back pain, also develop later neuropathic symptoms. CRPS (Complex Regional Pain Sydrome I,II) should be noted as a special form of neuropathy, which is mainly caused by minor injuries, and its pathophysiology is not perfectly understood, but it is assumed that immune reactions have a key role in it
(According to the now obsolete terminology CRPS I. was called Reflex Sympathetic Dystrophy, while CRPS II. was named Causalgia). It must be emphasized that, the loss of life quality is the main adverse effect of neuropathic pain during its long course (measured by e.g. QUALY=Quality Adjusted Life Years, or DALY=Disability Adjusted Life Years). As a chronic, progressive disease, most of the patients develop secondary comorbidities (the most common being secondary depression, anxiety, insomnia etc.). 1.3 The symptoms of neuropathic pain
A damage to the nervous system has two potential consequences: 1. loss of the somatosensory functions 2. abnormal (extra) perceptions. Therefore traditionally the symptoms of neuropathies are categorized into negative (loss of function), and positive (abnormal extra functioning) symptoms.
A negative symptom can be for example the loss of various sensory modalities (tactile, sensory etc.), hypesthesia (decreased pain perception), loss of vibration sensing. Though the patient experience these symptoms, and they indeed form an obstacle in the everyday life, but they are all painless. Thus the patients sooner or later habituate to the changed bodily perception (e.g. they switch to use their other, more skillful hand).
The positive symptoms on the other hand are always disturbing. The patients can not habituate the continous, uncomfortable, painful sensation, their life quality deteriorates. During the long course of the disease most of them will at one point or another develop the so-called „pain-personality”, which is practically a secondary depression. The most common positive signs are paresthesia (spontaneous, uncomfortable, but not clearly painful sensation), dysesthesia (spontaneous,
painful
sensation,
„pins
and
needles”,
burning
feeling),
hyperalgesia (decreased pain threshold), allodynia (painful sensation caused by normally non-painful stimuli e.g. mild tactile, thermal).
Fig 1.: The types of neuropathic pain on the basis of their intensity and causing factor. After: Cervero F, Laird JMA Mechanisms of touch-evoked pain (allodynia): a new model. Pain 1996 68: 13-23.
1.4 Special remarks on phantom limb pain It is a long-standing clinical experience, that patients who have lost a limb due to injury/operation often complain about a peculiar feeling as if the lost, „phantom” limb would be still the part of their body. This sensation is varying widely among the affected, it can be as simple, as the incorrect proprioception (sense of position), but it can also manifest itself as severe pain, dysesthesia, numbness, prickle as well. Phantom limb pain is defined as incorrect nociceptive stimuli arising from a no longer existing extremity. This phenomen is affecting in varying degree, but approximately two third of amputated patients, therefore it is a very common complication after the loss of a limb. The pathopysiological basis of phantom limb
pain is similar to other neuropathies, with a few unique characteristics. In phantom limb pain the primary lesion is the damage of the axons in the peripheral nervous system, which is in turn further worsened by central maladaptive changes. It is an interesting fact, that among those who suffered the loss of a limb at a younger age, the incidence of phantom limb pain later on is much less common.
2. Pathogenesis 2.1 About the etiology of neuropathic pain in general
When classifying peripheral neuropathies, we generally differentiate mono- and polineuropathies
(whether
one
or
several
nerves
are
affected).
The
mononeuropathies are mostly caused by injuries or compression. The latter one is most commonly encountered in clinical settings as carpal tunnel syndrome. The polineuropathies
have
mostly metabolic
(e.g.
diabetes)
or
toxic
(e.g.
chemotherapy) origin. The immune-mediated neuropathies are far less common, even their most common form, the Guillain-Barré-syndrome has only an incidence around 1-2/100 000/year. There can be three distinct pathophysiologic processes in the background of peripheral nerve damage. One of them is the so-called Wallerian degeneration, in which case the neural (axon, myelin) and other (epi, peri, endoneurium) parts of the nerve are damaged simultaneously (a.k.a. neuronopathy). This is mostly caused by physical injury. In this case, the complete healing is unlikely. Spontaneous recovery is incomplete mostly, usually caused by collateral neurotransmission by an other nerve fiber (axonal sprouting). Sadly, this mechanism is not only inefficient, but by establishing incorrect connections between axons carrying different modalities, it becomes also a key source of painful symptoms (like dysesthesia).
Normally the different sensory modalities are conveyed well-separated from each other to the CNS
If the myelin sheath is damaged (myelinopathies), the axons will be no longer isolated, and the action-potentials can abnormally propagate, which is the source of pathologic painful sensations.
In case of the injury of a peripheral nerve (mostly due to acute trauma), the healing is rarely adequate. Some of the distal axons will form incorrect connection, whereas those that can not reconnect will eventually perish. In the example above the conductance of painful and heat stimuli ceases, and the the tactile decreases (negative symptoms). On the other hand the incorrect connections make it possible to convey tactile and heat stimuli incorrectly as painful signals (positive symptoms).
Fig 2.: The mechanism of the development of dysesthesias in peripheral neuropathies
An other possible mechanism is primary demyelinisation (a.k.a.: myelinopathy). In this case the lesion affects principally the myelin sheath, while the axons are initially unaffected. The loss of the myelin leads to the impairment of saltatoric neurotransmission, slower conductance of action potentials, in the most severe cases: complete blockade. Axonal neuropathy is the rarest form, but it is infamous for its devastating effect. Its first step is the damage of the axons, but the underlying cause is currently only partially understood (endogenous toxic substances, and the impairment of the axonal flow are the assumed triggering factors). The three main mechanisms are summarized on Fig 3.
Fig 3.: Types of peripheral nerve damage that lead to neuropathic pain
When considering the main symptoms, we can differentiate motor, sensory, autonomic, and mixed neuropathies. The most notewothy forms are the sensory neuropathies, as many endemic diseases (diabetes, alcoholism, malnutrition) lead
to this condition, which affects a significant part of the population. However the other forms deserve attention as well. To underline this, we would like to mention as an example, that the neuropathy of the autonomic nervous system in diabetic patients at least doubles their cardiovascular mortality. The diagnostic approaches of neuropathies are well elaborated, taking the history, performing the physical examination, and some special diagnostic measurements (electromyography-EMG,
electroneurography-ENG)
usually
leads
to
the
diagnosis. For monitoring the progress, and to assess the severity of the disease, several questionnaires are available. The most widely used is the DN4 questionnaire (Douleur Neuropathique en 4 Questions). By asking two simple questions and performing two short physical examination, even a general practitioner can decide whether the patient suffers from somatic or neuropathic pain (Table 2.). [link: http://dn4.ca/local/files/pdf/en/questionnaire.pdf] We need to emphasize though, that even these days, the underlying disease can not be elucidated in 20-30% of the patients (idiopathic forms – origin currently unknown).
Overview of the DN4 questionnaire Questions
Answer/Sign
Explanation
Question 1.: Does the 1. Burning
Pain caused by cold/hot
pain have one or more of 2. Painful cold
stimuli normally below
the
the pain threshold, are
following 3. Electric shocks
characteristics?
characteristic
to
neuropathy. Question 2.: Is the pain 4.Tingling
Tingling and numbness
associated with one or 5. Pins and needles
are
more of the following
symptoms of neuropathy,
6. Numbness
typical
negative
symptoms in the same 7. Itching
and are rarely caused by
area?
somatic pain. Pins and needles pain is common in neuropathies.
peripheral
Examination 1: Is the 8. Hypoesthesia to touch pain located in an area 9. where
the
Hypoesthesia
The presence of negative
to symptoms
physical pinprick
dermatoma
in where
a the
examination
patient localises pain is a
may reveal one or more
characteristic feature in
of
neuropathies.
the
following
characteristics? Examination 2: In the 10. Brushing
This
examination
painful area, can the pain
reveal allodynia.
can
be caused or increased by: Assesment: During the test each „yes” answer means 1 point, the maximum is 10 points. 4 or more points suggest that the patient suffers from neuropathic pain.
3. Pathomechanisms
During the development of neuropathic pain, irrespectively of the original disease and the localisation of the primordial injury, secondary maladaptive changes occur at all levels of the nervous system. A main consequence of this for the practicing physician is, that these processes lead sooner or later to constant pain and resistance to analgesics. Therefore, we describe the key mechanism beginning from the periphery and proceeding towards the central nervous system (CNS).
Fig 4.: Schematic representation of the key mechanisms involved in the development of neuropathic pain, and their place in the process.
3.1. The sensitization of sensory nerve endings (peripheral sensitization)
The sensory nerve endings (nociceptors) are either non-myelinised C or thinly myelinised Aδ fibers. They can be specific to a distinct sensory modality (mechanical, chemical, thermal stimuli), or polimodal. The nociceptors can be activated by both external noxa and endogenous substances (inflammatory mediators, neurotransmitters, growth factors, etc.). After the axons of a peripheral nerve are damaged, begins the process called Wallerian degeneration (mentioned earlier). Then, distal from the lesion both the axon and the myelin sheath degrades, the necrotic tissue is infiltrated by macrophages and T-cells causing a sterile inflammation. The released inflammatory mediators and growth factors locally decrease the nociceptive threshold leading to hyperalgesia – a key symptom of neuropathies. This mechanism seems to be especially important in the development of CRPS I. and postherpetic neuralgia.
One of the most prominant pathways involved in the development of sensitization are the members of the Transient Receptor Potential (TRP) receptor family, which are situated on the nociceptors, andare activated in this process. The role of the TRPV1 receptor worths mentioning in particular. This receptor is activated by capsaicine (which causes the pungent taste of red pepper), but its „normal” activators are painful heat stimuli and several endogenous inflammatory mediators (lipoxygenase products, acidic pH etc.). After all it is not surprising that their increased activation leads to a distinct burning sensation in neuropathies. The role of the other receptors belonging to the TRP family (TRPA1, TRPM8) have not yet been clearly elucidated.
3.2 The abnormal, ectopic excitation of the sensory nerve endings
The altered excitability and spontanous discharge of nerve fibers has a key role in the development of the positive symptoms of neuropathy. On a cellular level this can be explained by the increased expression of the voltage-gated sodium channels. Therefore it is understandable, that drugs blocking the sodium channels (carbamazepine, oxcarbazepine, phenytoine, lidocaine) are often found to be beneficial in neuropathic patients. The tricyclic antidepressants (TCA) also have sodium channel-blocking effect, thus they can be used effectively in the treatment of neuropathic pain, whereas the selective serotonine reuptake inhibitors (SSRI), have no such effect.
3.3 Pro-nociceptive (pain sensation-increasing) changes in the spinal dorsal root (central sensitization)
The central endings of the pseudounipolar primary sensory neurons form synapses with the secondary sensory neurons in the spinal dorsal root. The main excitatory neurotransmitter of the central nervous system (and therefore also in the nociceptive system) is the glutamate, which has three known receptors (AMPA – which is linked to ion channel, the NMDA [N-metil D-aspartate] receptors, and the Gs/q proteinelinked metabotropic mGluR receptor). In the dorsal root the increased activation of the AMPA receptors, and the release of NMDA receptors from the physiologic blockade collectively leads to the increased excitability of the secondary sensory neurons. This in turn makes them excitable by not only the C and Aδ fibers, but also
by the Aβ fibers. This can result in continous pain sensation (pin-prick hyperalgesia), or pain evoked by normally non-painful stimuli (allodynia). Therefore it seemed to be a logical step to block the glutamate-receptors, but the clinical studies addressing this question ended with unconvincing results (memantine, dextrometorphan). Ketamine on the other hand was found to be effective in the treatment of several neuropathic pain syndromes.
3.4 The blockade of the spinal inhibitory system
The importance of the spinal inhibitory system was first highlighted by the so-called thermal grid-illusion experiment (1896). In this easily reproducable experiment warm and cold metal rods were placed next to each other in alternating pattern. If the experimenter touches only one rod at a time, he/she can feel the hot/cold stimulus, which is not uncomfortable (40/20
o
C). However by touching more rods
simultaneously, the experimenter will experience painful burning sensation. The cause of this phenomen is that the fibers conveying the warm stimuli block in the dorsal root the Aδ fibers conducting the cold stimuli. This in turn causes that the C fibers conducting painful heat stimuli are released from the physiologic blockade, and wrongly they will conduct painful heat stimuli to the central complexes. This phenomen is of great importance in the development of neuropathic burning pain. An other important mechanism is the decreased functioning of the descending inhibitory pathway of the nociceptory system (the role of the endomorphins is particularly emphasized). In the meantime, the cholecystokinine-receptor expression increases in the dorsal root (cholecystokinine antagonizes the effect of the endomorphins and exogenous morphin as well). The therapeutic effect of several drugs can be explained by the enhancement of this inhibitory mechanism (SNRI-s, SSRI-s, TCA-s, duloxetine, venlafaxine, valproate etc.) Among the nonpharmaceutical treatments the Transcutaneous Electric Nerve Stimulation (TENS), and the Spinal Cord Stimulation (SCS) also affects this inhibitory pathway.
3.5 Pain maintained by sympathetic activation
In case of sympathetically maintained pain, abnormal connections are formed between the sympathetic and sensory systems, which are physiologically well-
separated. Several studies have verified, that in neuropathic pain models the sympathetic afferents exert an inhibitory effect on nociceptive afferents in the spinal dorsal horn. This mechanism has a pivotal role in the development of complex regional pain syndrome, phantom limb pain, and traumatic neuropathies.
3.6 Central reorganization
The significance of the alterations that occur primarily or secondarily in the central nervous system was for a long time unexplained. The modern functional imaging techniques (MRI tractography, Diffusion tensor technique, PET etc.) made a huge impact on this field. It is certain, that every pain syndrome that becomes chronic (which is characteristic of neuropathies) induces secondary changes in the CNS. However, in particular neuropathic pain syndromes (e.g. post-stroke neuropathy) the CNS lesion is the primary trigger. The neuronal rearrangement that occurs in the cortex is rarely beneficial. The defined somatotopic (correspondence of an area of the body to a specific point of the cortex) pattern can be altered. This is especially marked in phantom limb pain, in which case this leads to a more intensive pain sensation. Besides the cortex, the deeper cerebral structures can also be affected, e.g. the periaqueductal gray matter (PAG), and the rostral ventral medulla (RVM). Nevertheless whether these changes are definitely pro- or antinociceptive is still a matter of debate. Unfortunately none of the currently available medications target this mechanism, but there are some potential therapeutic methods in the early clinical research (e.g. transcranial magnetic stimulation) that seem to have a beneficial effect in these conditions.
3.7 The characteristics of the development of phantom limb pain
Traditionally the development of phantom limb pain was mainly attributed to the ectopic stimuli arising from the peripheral (stump) neuroma. In this case the on the end of the injured nerve the fibers become demyelinised, and abnormal connections are formed between them (ephactic crosstalk). The spontaneous excitability of the fibers also increases. The early clinical evidences showed, that local anesthesia rarely gives relief to the patients. This raised the idea, that in the development of phantom limb pain
reorganization processes in the central nervous system might be also involved. On spinal level the dorsal root ganglion (DRG) plays the key role, as this is the source of ectopic stimuli, and pathologic interactions between the sympathetic and sensory nervous systems. This explains also the fact, that the symptoms of phantom limb pain are worsened during emotional stress. The long-lasting abnormal stimuli arising from the periphery will sooner or later lead to permanent changes in the responsiveness or the DRG neurons: resulting in the development of central senzitization. An other important change is the down-regulation of the opioid receptors, the decrease of GABAergic neurotransmission, and the increased expression of Substance P (SP). The supraspinal changes form the last part of this process. After their development the phantom limb pain becomes chronic, its curability decreases. The dislocation of the representational areas of the primary somatosensor and motor cortex is characteristic, as well as the reorganization processes in the thalamus. It is an interesting fact that in several cases the character of phantom limb pain is akin to the somatic pain felt there before the loss of the limb. This gave researchers the idea, that these so-called „pain memories” can be important factors in the development of phantom limb pain. Clinical studies have also verified that the best prognostic factor of phantom limb pain after amputation is chronic pain felt in the affected limb, before its loss (though we have to mention that patients, who have lost their limb due to acute injury were not enlisted in this study).
4. Pharmacotherapeutic management of neuropathic pain When discussing the pharmacotherapy of neuropathies, it is important to note that nonsteroid anti inflammatory-analgesic drugs (NSAID) which are the most popular and widely used OTC painkillers, are largely ineffective in neuropathic pain syndromes. However their several side-effects can result in severe complications (which is often encountered in patients who try to cure themselves). At the same time the formerly widely used term of „morphine-resistant pain” is unsubstantiated and incorrect, therefore it should be avoided in the future. The main challenge is that the currently available therapeutic options are symptomatic at best. Moreover even our most up to date drugs like duloxetine and pregabaline give significant relief only in one patient out of four, and even in their case they only give approximately 50% pain relief. 4.1 Drug groups used in the treatment of neuropathic pain
4.1.1 Drugs used in the first line
The tricyclic antidepressants (amytriptyline, nortryptyline, imipramine, desipramine) mediate their effect mainly by the central inhibition of the monoamine reuptake. Unfortunately, their clinical use is limited by their numerous and severe side-effects. Their effect is the increase of the concentration of monoamines (noradrenaline, dopamine, serotonine) in the synaptic cleft. Therefore the monamines effect is facilitated in the descending pain-inhibitory pathway. Several clinical studied provided evidence of their effectiveness in HIV-associated and chemotherapy-induced neuropathies. Their antidepressant effect is also beneficial, as the mood disorders are the most common comorbidity of chronic pain syndromes. Their relatively low price is also an advantage (practically all of them are available as generic drugs), as well as their convenient dosage (1x1 daily). Unfortunately their side-effects, especially on the cardiovascular system, and their muscarinic receptor agonism (dry mouth, orthostatic hypotension, obstipation, urinary retention) make them also dangerous and hard to tolerate. Their cardiotoxic effect must be also taken into account, as they can only be used in lower doses and with regular ECG controls in patients with ischemic heart disease (N.B. diabetes-IHB is connected!) or ventricular conductive abnormalities.
Venlafaxine and duloxetine act through similar mechanism, but they selectively block the reuptake of noradrenaline and serotonine (selective serotoninenoradrenaline reuptake inhibitors-SSNRI). They were found to be particularly beneficial in diabetic neuropathies. Regarding their side-effects duloxetine was found to be safe, as it has no adverse cardiac effects, though it rarely causes nausea, whic can be avoided by gradual increase of the dose at the beginning of the therapy. Venlafaxine on the other hand can lead to conductance abnormalities and elevated blood pressure, therefore the dose must be carefully adjusted at the beginning and the end of therapy,
Gabapentine and pregabaline were originally marketed as antiepileptics, but today they are one of the most favoured and prescribed drugs in neuropathies as well. They are safe, largely free from untoward side-effects. Currently they form the first step in the pharmaceutical treatment of most neuropathic pain syndromes
in developed countries. Despite the fact that they were developed to be GABA analogues, in neuropathies the inhibition of voltage-gated calcium-channels is their main effect. This in turn leads to the blockade of neurotransmitter-release. As both drugs are well-tolerated and have no dangerous interactions they are especially advantageous for elderly, comorbid patients. However both can cause vertigo or sedation in the beginning, which can be mostly avoided by the slow titration of therapeutic dosage. In patients with severe impairment of renal functions, increased caution, if necessary dose reduction is required (the creatinine-clearance is used to determine this). The bioavailability of creatinine surpasses that of the gabapentine, thus a faster onset of effect can be expected (as gabapentine has nonlinear pharmacokinetics, the therapeutic dose can be reached only slowly and stepwise, pregabaline has linear pharmacokinetics which makes its dosage easier).
Lidocaine is a well known anesthetic, but it is also useful in neuropathies (it blocks the voltage-gated sodium channels mentioned earlier). Unfortunately its low plasma half-life limits its applicability. Therefore it is mainly applied topically, with sometimes surprisingly long-lasting analgesic effect. The 5% lidocaine patch was found to be effective and well tolerated in postherpetic neuralgia, and a variety of neuropathic allodynias. Because this way only a small amount of it is absorbed, it is largely free from systematic side-effects. The 5% lidocaine gel is also effective, but is much cheaper than the patch. On the whole we can expect relief from topical lidocaine in peripheral neuropathies, but is absolutely ineffective in centrally maintained pain syndromes.
4.1.2 Drugs used in the second line (in some cases they can be in the first line) Tramadol mediates its analgesic effect through a dual mechanism: as a μ-opioide receptor agonist it blocks the ascending nociceptive pathways, and it also activates the descending monoaminergic inhibitory system (noradrenaline and serotonine reuptake inhibition). The analgesic effect is potentiated by these two mechanisms. It can be used effectively in postherpetic neuralgia, diabetic polineuropathy, an almost all painful polineuropathies. It is weaker analgesic when compared to the „classical” opioids (morphine, oxycodone etc.), but its effect has similarly fast onset, and the risk of addiction is much lower. Its side-effects are similar to the
other opioids, it can cause seizures and when combined with SSRI or SSNRI drugs can produce life-threatening serotonine-syndrome.
Tapentadol is a novel opioid agonist with similar mode of action. It was found to be effective in the management of diabetic polineuropathy. As it is a relatively new, original drug, its cost is higher.
The debate about the role of the other opioid drugs in the therapy of neuropathies is far from settled. In a comparative study, in which patients with postherpetic neuralgia were sequentially treated with opioid, tricyclic antidepressant, and placebo, the patients unambigously preferred the opioid. Among their several side effects, the obstipation, nausea, and sedation must be emphasized. During the chronic treatment, dependance occurs also almost unescapably (therefore at the end of therapy the dose must be reduced gradually). Considering these limitations, opioid painkillers are today usually advised only if the analgesic effect of first-line drugs is no longer sufficient. There are however some exceptions, when opioids can already be used in the first line of treatment (usually tramadol). Some examples are acute neuropathy, neuropathy caused by malignancy, acute exacerbation of chronic neuropathy, and transitionally until the onset of the effect of first-line drugs. Special care must be taken in case of patients who are susceptible of drug-abuse, patients with chronic airway diseases. Opioids with effect lasting longer (sustained release preparations) are squarely advantageous.
4.1.3 Third line drugs (drugs used mostly in some distinct neuropathic entities)
Carbamazepine is an antiepileptic drug, which has strong sodium and less potent calcium channel-blocking ability. It is relatively popular in the outpatient treatment, and is a first line drug in trigeminal neuralgia. It is also beneficial in some other froms of neuropathy, like postherpetic neuralgia and herpes zoster.
Lamotrigine is part of the second-line treatment in post-stroke neuropathy, whereas there is less evidence about the value of valproate, topiramate, and other
anticonvulsants. The recent results show that they might be useful in the management of diabetic, HIV-induced, and post-stroke neuropathy.
NMDA-receptor anatgonists seem to mediate they effect through the inhibition of central sensitization. Ketamine is efficient in the treatment of postherpetic neuralgia,
whereas
the
orally
administrated
NMDA
antagonists
(dextrometorphane, memantine etc.) were found to be useful in diabetic polineuropathy.
The potential of selective serotonine reuptake inhibitor (SSRI) drugs is not evident. In the clinical studies paroxetine and citalopram were found to be moderately beneficial, while fluoxetine proved to be ineffective when compared to placebo.
4.2 The management of neuropathies caused by lesions of the central nervous system Far less clinical data are available about the management of the neuropathies, that are caused by a primary lesion in the central nervous system, or in which the pain is maintained by mostly central mechanisms (though as we have seen earlier, all CNS changes are at least partially involved in all neuropathies). According to recent evidence, in post-stroke neuropathy the TCA, SNRI, and Ca2+channel blocker drugs are useful. In neuropathy related to spinal cord injuries, the Ca2+-channel blockers and tramadol were found to be effective. The endocannabinoid system is also a promising target in sclerosis-multiplex-associated neuropathies (see later). 4.3 About the therapy of phantom limb pain The general observations about the treatment of neuropathies are especially true t phantom limb pain: the effectiveness of the therapy is insufficient, regarding both the pharmaceutical and other (e.g. nerve stimulation) treatments. The expected result is modest at best, and few and mostly non-controlled clinical study data are available about the management of these conditions. The analgesic effect seldom surpasses 30% (measured by e.g. visual analogue scale).
The opioids, ketamine, dextrometorphane and gabapentine were found to have significant analgesic effect. There are less available data about the usefulness of the topical lidocaine therapy.
5. EBM (Evidence Based Medicine) data 5.1 Clinical studies in neuropathic pain
It is important to note that we only have verified data about a minority of neuropathic conditions. The randomized, controlled trials (RCT) performed so far, mainly
focused
on
either
postherpetic
neuralgia,
or
painful
diabetic
polineuropathy. It is also disadvantageous, that there are hardly any cross-over studies, in which different drugs/preparations would be self-controlledy compared to each other.
It is therefore essential to be critical about or current knowledge of therapeutic modalities, as much of that will certainly have to undergo revision in the future. A good example of this is HIV-associated neuropathy, which is surprisingly resistant to
first-line
drugs.
Chemotherapy-induced
neuropathy,
and
lumbosacral
radiculopathy are also resistant to analgesics.
We have to emphasize, that in the management of neuropathies, only the mechanism-centered approach could lead to success, and when choosing the adequate therapeutic modalities, individual treatment, tailored to the patients disease and symptoms is necessary.
5.2 Monotherapy vs. combinations
It is a long-standing tradition in medicine, that the pharmacotherapy of a patient must be kept as simple as possible, as otherwise the compliance would decrease dramatically. Therefore it is an understandable intention to keep the patient at monotherapy, and employ the simplest, most easily remembered administration protocol (e.g 1x1 daily). Unfortunately as we have seen earlier, the development of the neuropathic pain is a complex process, which automatically means that we
have a lot of targets as well. Aiming for only one target at a time rarely provides acceptable life quality for the patient. The proper approach therefore is to start with monotherapy, but if the analgesic effectproves to be insufficient, we have to switch early to the combination therapy with a drug acting on a different target (but always carefully considering the possibility of interactions!). Unfortunately there is only a limited evidence concerning the best drug combinations. According to recent studies gabapentine + sustained-release opioids, or TCA + gabapentine combinations make it possible to decrease the dose of both drugs, though clear and concise guidelines are badly lacking. Pregabaline can be succesfully combined with gabapentine, TCA, and tramadol. The 8% capsaicin patch (see later), can be combined with almost anything (if there are no contraindications).
5.3 Clinical recommendations about the drugs currently on the market
Table 4. Drugs used in the most important neuropathic pain syndromes, grouped by their reccomendation level Disease Diabetic neuropathy
First line
Second line
duloxetine
tramadol
gabapentine
opioids
pregabaline TCA venlafaxin ER Postherpetic neuralgia
gabapentine
capsaicine patch
pregabaline
opioids
TCA Lidocaine patch Trigeminal neuralgia
carbamazepine
non-pharmaceutical
oxcarbazepine
treatment intervention)
Central pain syndromes
gabapentine
cannabinoids
pregabaline
lamotrigine
(surgical
TCA
opioids tramadol
Neuropathies caused by gabapentine
TCA
malignancy
tramadol opioids pregabaline
Radiculopathy
TCA opioids
Phantom limb pain
tramadol
gabapentine opioids
Note: According to the 2010 guideline of EFNS (European Federation of Neurological Societies)
If we can no longer guarantee acceptable life quality by pharmacotherapy, in certain neuropathic diseases other, non-pharmacotheraoeutic options (mostly nerve stimulation) can be started (for details see Table 5.).
Table 5. Recommendations about the application of non-pharmaceutical treatments in the analgesic-resistant neuropathic conditions Etiology Spinal cord injury, post-stroke pain
Treatment Stimulation of the motor cortex by transcranial
magnetic
stimulation
(rTMS) Phantom limb pain
Deep brain stimulation of the thalamus and PAG
CRPS, pain arising after surgery of Epidural stimulation of the spinal dorsal the spinal column („failed back cord (SCS) syndrome”) Facial pain, post-stroke pain
Stimulation of the motor cortex (MCS)
Source: Cruccu et al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neur 2007;14:952-70
5.4 Practical remarks on the therapy
According to the clinical experience, if the pain is neuralgic (shock-like) then the best results can be expected from carbamazepine. If for some reason the patient does not tolerate it, then oxcarbazepine, gabapentine, pregabaline, sometimes lamotrigine are used. In chronic, non-neuralgic pain the TCA drugs are recommended, but if they are not tolerated, then duloxetine, venlafaxine, gabapentine, or pregabaline are also useful. The Quatenza capsaicine-patch can also be used in non-diabetic peripheral neuropathies. Until the onset of sufficient analgesic effect, the temporary use of mild sedatives, benzodiazepines is also accepted to relieve the patient from the accompanying sleeping disorder and stress. As we have mentioned earlier, the complete absence of pain is a rarely achieveable goal in chronic neuropathies. Thus, it is useful to make a therapeutic agreement with the patient. For example: if we determine the actual pain of the patient before the beginning of the therapy by Visual Analogue Scale (0-complete absence of pain, 10-unbearable pain), we can mark a target value (which should never be zero in the first step). It is important to detect early those patients, that can longer expect acceptable life quality from pharmacotherapy. In their case functional neurosurgical interventions can help.
5.5 About the effectiveness of treatment
When comparing the effect of different drugs, one of the most important indicator is the Number Needed to Treat (NNT). NNT shows us how many patients we have to treat lege artis with a given medicine, to reach definitive improvement in one of them (that means in our case less intensive pain). Traditionally in analgesic research „definitive improvement” is described as at least 50% decrease of pain sensation. According to clinical experience, NNT value is around 3 in neuropathies even in case of the most potent analgesics (TCA, sodium channel-blockers, opioids) (Fig. 5) – that means that we can only expect significant improvement in one subject out of three properly treated(!) patients! Therefore it is understandable, how limited our current therapeutic modalities are. It is especially true if we mention that even among patients who react to therapy, the effect is – nearly always – partial.
Fig. 5: Number Needed to Treat (NNT) of some of the most commonly used systemic drugs in neuropathies. Based on: Finnerup et al. Algorithm for neuropathic pain treatment: an evidence based proposal Pain 2005 118: 289-305.]
6. Potential new therapeutic modalities (clinical and preclinical data)
The modest results of pharmacotherapy in the management of neuropathic pain can be explained by the fact, that nearly all drugs currently on the market were discovered by the serendipity method (literally: „happy accident”), sometimes only after the drug has already entered the market with different indications (e.g pregabaline was originally developed as an antiepileptic, while TCAs as antidepressants). It is very hard to determine in neuropathic conditions, that even if a drug passes the preclinical phase (which also has many pitfalls due to the difficulties of animal experiments), that what kind of patients should we involve in the clinical trial. An
other problem is, that what can we measure at all, what kind of indicators can help us to determine the presence/lack of effect. Nowadays, mostly patients with postherpetic neuralgia or diabetic polineuropathy are chosen for the Phase II,III trials, as these are the most common neuropathic disorders. The better understanding of the cellular and receptorial pathways responsible for the transmission of pain made in the last two decades possible, to start the development of specific drugs against the most important mechanisms/target molecules (Table 5.)
Table 6. Novel targets (drugs, mechanisms currently in clinical/preclinical research) Glutamergic receptors
Phase I, II clinical trials with agonists acting on Metabotropic, AMPA, or NMDA receptors
TRPV1 receptor
Phase I, II, III studies with different antagonists, and with some agonists that permanently activate the receptor and desensitize the nerve ending. The recently approved Qutenza dermal patch contains 8% capsaicine. By opening the TRPV1 ion channel, the large Ca2+ influx causes permanent desensitization of the nerve ending. The patch can be applied to the painful area after local anesthesia, and it still requires cautiousness. Its effect is long-lasting (approximately 12 weeks after a 0,5-1 h treatment session). Based on evidence gained so far it is beneficial in
a
wide
neuropathies
variety
of
peripheral
(postherpetic
neuralgia,
AIDS). It is contraindicated in diabetic neuropathies, as it presumably decreases skin microcirculation, thereby promoting ulcerations. CBr1 cannabinoid receptor
Phase I, II studies with agonists in central
pain syndromes and sclerosis multiplex Voltage gated potassium and sodium- Retigabine channels
(Trobalt/Potiga,
Valeant
Pharmaceuticals) is an agonist on the KCNQ voltage gated potassium channels. It was approved in 2011. Its main indication is currently the treatment of partial epilepsies, but it holds out a promise to be a useful tool int he management
of
neuropathies
and
migraine as well. Lacosamide (Vimpat, UCB) is a novel antiepileptic drug, which acts on the voltage-gated
sodium
channels.
The
results obtained so far were unconvincing regarding its effect, in phase I, and II. studies only marginal difference was found when compared to placebo. Ralfinamide (Newron Pharmacuticals) is a dual-action voltage gated sodium channel
blocker/MAO-inhibitor.
The
preclinical experiments were so far convincing, but in the clinical phase (SERENA trial) they could not find any remarkable
effect
in
patients
with
neuropathic-radiculopathic pain. Botulinum toxin
The potential of intradermal application of botulinum toxin can not yet be decided. In some studies it was found to be effective in the treatment of neuropathic mechanical allodynia, whilst other trials did not manage to verify this.
Gene therapy, other possibilities
All of these developments are currently in the preclinical phase, their apperance in
clinical practice can only be expected on long-term. Among the ideas so far raised, the intrathecal/intraspinal introduction of the genes of endogenous analgetic peptides (endorphines, enkephalines) with viral vectors can be a promising tool. The direct introduction of the glutamateddecarboxylase gene near the peripheral nerves was also suggested.
Questions
Simple choice
1. Which statement is true? A – In the development of neuropathic pain the damage of the peripheral nervous system is always involved. B – The prevalence of neuropathic pain in the european population can be as high as 7-8%. C – It is advised to begin the treatment of neuropathic pain with NSAIDs (NonSteroide Antiinflammatory Drugs). D – Opioids are ineffective in neuropathies, therefore they are not advised. E – In most neuropathic patients, monotherapy alone guarantees complete absence of pain.
(B)
Explanation: The correct answer is B, as the prevalence of neuropathic patients in the european population as around 7-8% according to current estimations. Answer A is incorrect, as neuropathies can arise also as a consequence of purely central lesions (e.g. post-stroke neuropathy). The NSAIDs are ineffective in neuropathies, and should be avoided. Opioids on the other hand are useful, if
applied in correct dose and well-indicated. Total absence of pain is rarely possible in neuropathies, especially not with monotherapy.
2. Whic statement is false? A – Peripheral senzitization is also involved int he development of hyperalgesia. B – TRPV1 receptor can be activated by noxious heat stimuli. C – Alterations of the CNS are rare in neuropathies, and can easily be treated with drugs. D – Glutamate is an important excitatory neurotransmitter of of the nociceptive system.
(C)
Explanation: As neuropathic pain is usually long lasting, secondary maladaptive changes of the CNS develop very often, which are surprisingly resistant to therapy.
3. A patient comes to you, whose main complain is a severe pain (Visual Analogue Scale: 9), which after taking the DN4 questionnaire appears to be neuropathic. The patient has been taking NSAIDs for two months for relief – without success. What do you do in this situation? A – Increase the dose of NSAID, ask for neurosurgical expert opinion. B – Forbid NSAIDs, prescribe opioide instead. C – Leaves the dose of the NSAID unchanged, supplements the treatment with carbamazepine and tramadol, directs the patient to psychiatry due to presumed drug-abuse D – Directs the patient to neurology, forbids further NSAID self-medication.
(D)
Explanation: NSAID treatment in this case is obviously useless, but its side-effects (e.g. gastrointestinal erosions) can even further worsen the patients condition. In the management of neuropathic pain we have to seek after an early diagnosis of the etiology, as the causing factor can easily be an underlying severe disease (e.g. malignancies), which calls for neurology specialist. As long as the etiology is
unclear, only careful pharmacotherapy is allowed (certainly noth with opioid analgesics).
7. Which one of the following drugs should be given in the first line to patients with trigeminus neuralgia? A – Tramadol B – Gabapentine C – Capsaicine-patch D – Carbamazepine E – Lamotrigine
(D)
Explanation: In trigeminus neuralgia carbamazepine is the first option.
8. Which one can be only carefully used in the treatment of patients with narrowed renal functions? A – Carbamazepine B – Lidocaine patch C – Gabapentine D – Tramadol E – Duloxetine
(C)
Explanation: As gabapentine has a non-linear pharmakokinetics, it can easily accumulate in patients with damaged renal functions.
Relation analysis: A – true-true, interrelated B – true-true, not interrelated
C – true-false D- false-true E – false-false
9. Allodynia belongs to the positive symptoms of neuropathic pain, as in allodynia physiologically non-painful stimuli lead to painful sensation.
(true-true, interrelated - A) Explanation: Allodynia is a typical „extra sensation”, therefore a positive symptom, which is characterized by the pain sensation caused by normally nonpainful (e.g. tactile) stimuli.
10. Axonopathies have better recovery rate than myelinopathies, as in myelinopathies pathologic pathways are formed between the different axons.
(false-true - D)
Explanation: Primary axonal damage has a very low spontaneous recovery rate. In myelinopathies the axons lose their „insulation”, so action potentials can abnormally propagate.
11. The DN4 questionnaire helps the division of neuropathic and somatic pain, as NSAIDs are always effective in somatic pain.
(true-false - C)
Explanation: With the DN4 questionnaire the caharcter of the pain can be described by a few simple questions and physical examinations. NSAIDs are of course not always effective, even in somatic pain syndromes.
12. In the management of neuropathies the early combination therapy is effective, as the with the presently available drugs complete absence of pain can be achieved.
(false-false -E)
Explanation: In neuropathic pain the treatment is usually started with monotherapy. If the analgesic effect later proves to be inefficient, we step further to combination therapy. Complete absence of pain is rarely possible with the currently available medications.
13. The mood stabilizing effect of tricyclic antidepressants is beneficial in neuropathic patients, as they are hardly tolerated due to their relatively common side-effects.
(true-true, not interrealated - B)
Explanation: The mood stabilizing effect of TCAs is useful, as in patients suffering from chronic pain secondary depression is common. Irrespectively of this fact, their severe and frequently encountered side-effects limit their use.
Multiple choice questions A – 1,2,3 is true B – 1,3 is true C – 2,4 is true D – only 4. is true E – All answers are true
14. Which ones are positive symptoms from the following? 1. Allodynia 2. Paresthesia 3. Hyperalgesia 4. Hypesthesia
(1,2,3 - A) Explanation: Hypesthesia means diminished pain sensation in an affected area, therefore it belongs to the negative symptoms. 15. Which drug combinations are advantageous in the treatment of neuropathies? 1. Tricyclic antidepressant + gabapentine 2. Tramadol + tapentadol 3. Pregabaline + tramadol 4. Tramadol + SSRI (1,3 - B) Explanation: Tramadol and tapentadol are both weak opioids, therefore their combination would not lead to additional benefit. Tramadol can cause dangerous serotonine-sydrome when combined with SSRIs, therefore this combination must definitely be avoided. 16. In which is case is the utmost carefulness requiered in the use of tricyclic antidepressants? 1. Neuropathy caused by AIDS 2. If the patients has atrial fibrillation, and ventricular extrasystoles are present on the ECG 3. If according to the medical history, the patient received medical treatment due to depression earlier. 4. If the patient whose hypertension is long time known, show positive results on oral glucose tolerance test.
(2,4 - C)
Explanation: The use of TCAs is especially risky if the patient has ventricular conductance abnormalities. Long standing hypertension and impaired glucose tolerance suggests metabolic syndrome and IHD, in which case TCAs could be dangerous due to their cardiotoxicity.
17. In which case would you NOT apply capsaicine dermal patch? 1. Diabetic polineuropathy
2. Postherpetic neuralgia 3. Post-stroke depression 4. Posttraumatic mononeuropathy
(1,3 - B)
Explanation: Capsaicin can decrease the microcirculation of the skin in diabetic patients, thereby promoting the formation of ulcers. Post-stroke depression is caused by purely the lesion of the central nervous system, thus the topical application of capsaicine would be ineffective. Comparison A – 1. is bigger than 2. B – 2. is bigger than 1. C – equal 18. In which case exists a higher risk of developing phantom limb pain? 1. Amputation of a limb due to sudden injury in childhood 2. Surgical amputation of the same limb due to chronic, painful disease (e.g. Buergerdisease) in old age. (B) Explanation: If the amputation of the limb is preceeded by long-lasting somatic pain in the same region, then the probability of later developing phantom limb pain is much higher („pain memories”). It is less proved, but phantom limb pain was found to be less commmon if the amputation took place in the childhood. 19. Which neuropathic disease is more common? 1. Carpal tunnel-syndrome 2. Guillain-Barré-syndrome
(A)
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