NEUROPATHIC PAIN

DR MOHAMMAD A.S. KAMILCONSULTANT NEUROLOGIST

Neuropathic pain resulting directly from a lesion or disease affecting the somatosensory system.

diabetic polyneuropathies, postherpetic neuralgia, trigeminal neuralgia, and central poststroke or spinal cord injury pain.

Traumatic or postsurgical neuropathies and painful radiculopathies are also common conditions in the general population.

Paresthesia are abnormal spontaneous or stimulus-independent sensations, often described as tingling or compared to a limb that has fallen "asleep.

Dysesthesia refers to an unpleasant abnormal sensation that can be spontaneous or evoked.

allodynia to pain following contact by a normally non-noxious stimulus.

hyperalgesia to exaggerated pain from a noxious stimulus Hyperpathia is a complex sensory experience

characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, in a patient who initially perceives the stimulus as less intense.

MAJOR MECHANISMS INVOLVED IN NEUROPATHIC PAIN

Peripheral Mechanisms: Abnormal (ectopic) neuronal activity has been reported in

primary afferents and in the dorsal root ganglion and appears to be mainly related to dysregulation of the synthesis or the functioning of sodium channels (notably the tetrodotoxin resistant channels), although potassium channels may also be involved.

Nerve injury also induces upregulation of several receptor proteins, including transient receptor potential vanilloid 1 (TRPV1).

TRPV1 is located on subtypes of peripheral nociceptive endings and is physiologically activated by noxious heat, among other stimuli.

After a nerve lesion, TRPV1 is upregulated in uninjured C fibers and downregulated in injured nerve fibers.

CENTRAL MECHANISMS

Several major types of modifications can induce pathologic activation of central nociceptive neurons:

1)modification of the modulatory controls of the transmission of nociceptive messages;2) anatomic reorganization (neuroplasticity) of the central nociceptive neurons and thus their pathologic activation; 3)microglial activation; and 4) central sensitization (hyperexcitability) of nociceptive neurons.

Central sensitization probably depends critically on intracellular changes induced by the activation of NMDA receptors or other receptors (ie, glutamate metabotropic receptors) by excitatory amino acids released by primary afferents.

Because of the multiplicity of mechanisms, it is unlikely that NP is related to only one mechanism.

CURRENT DRUG TREATMENT FOR NEUROPATHIC PAIN .

Tricyclic antidepressants Nortriptyline ,Desipramine ,Amitriptyline Inhibition of reuptake of monoamines, block of sodium

channels, anticholinergic. Somnolence, anticholinergic effects, weight gain. Cardiac disease (ECG), glaucoma,prostatic adenoma,

seizure, use Desipramine of tramadol. A: Diabetic neuropathy, postherpetic neuralgia

(PHN) B: Spinal cord injury/central side effects poststroke

pain, traumatic nerve lesions, cancer neuropathic pain

SEROTONIN NOREPINEPHRINEREUPTAKE INHIBITORS

Duloxetine ,Venlafaxine Inhibition of serotonin and norepinephrine reuptake.

Nausea (A: Diabetic neuropathy).

CALCIUM CHANNEL ALPHA-2-DELTA LIGANDS

Gabapentin,Pregabalin Acts on alpha-2-delta subunit of voltage-gated calcium

channels, which decreases central sensitization. Sedation, dizziness, peripheral edema,weight gain. Reduce dosages in renal insufficiency. Gabapentin:A: Diabetic neuropathy, PHN,cancer

neuropathic pain B: Spinal cord injury pain No clinically significant drug

interactions, improvement of generalized anxiety and sleep

Pregabalin:A: Diabetic neuropathy, PHN, spinal cord injury pain

TOPICAL LIDOCAINE

Lidocaine 5% plasters: Block of sodium channels Local erythema, itch, rash. No systemic side effects,potential

effect on allodynia. A: PHN 1 to 3 patches/3 patches.

Capsaicin patches 8% Transient receptor potential vanilloid 1

agonist Pain, erythema, elevated blood pressure due

to initial increase in pain. No systemic side effects, potential effects on

burning pain, itching, and allodynia. A: HIV neuropathy and PHN 1 to 4 patches to

cover the painful area, repeat every 3 months.

OPIOID AGONISTS

Tramadol Mu receptor agonist and inhibition of

monoamine reuptake Nausea and vomiting, constipation, dizziness,

somnolence. History of substance abuse, suicide risk, use of

antidepressants in elderly patients. Rapid onset of analgesic effect, effect on

inflammatory pain A: Diabetic neuropathy, phantom pain B: Spinal cord injury pain

Morphine, oxycodone,methadone, levorphanol

Mu receptor agonists (oxycodone may also cause k-receptor antagonism)

Nausea and vomiting, constipation, dizziness,somnolence.

Rapid onset of analgesic effect,effect on inflammatory pain

A: Diabetic neuropathy, PHN, phantom pain

OTHER NEUROPATHIC PAININDICATIONS

pregabalin is now the drug of choice for SCI pain.

A Class I trial showed no superiority of duloxetine over placebo on the primary outcome of central pain due to stroke or SCI, but several secondary outcomes, including allodynia to brush and cold, favored duloxetine.

Studies of gabapentin have found positive results in Guillain-Barre´ syndrome and cancer NP and discrepant results in phantom limb pain.

Opioids and tramadol have been found to be efficacious for phantom limb pain.

amitriptyline has been found to be efficacious for cancer neuropathic pain.

A recent large-scale study using an enrichment phase demonstrated no benefit of pregabalin for lumbosacral radiculopathy.

EMERGING TREATMENTS FORNEUROPATHIC PAIN

Botulinum Toxin Type A: Several lines of investigation have suggested that botulinum toxin

type A (BTX-A), a potent neurotoxin commonly used for the treatment of focal muscle hyperactivity, may have analgesic effects independent of its action on muscle tone, possibly by acting on neurogenic inflammation.Such mechanisms may be involved in some cases of peripheral NP.

Three single-center RCTs reported the long-term efficacy of a series of subcutaneous injections of BTX-A (from 100 to 200 U) injected into the painful area among patients with mononeuropathies (traumatic or related to herpes zoster) and patients with diabetic PPNs.

Interestingly, in these two studies, the onset of efficacy (about 1 week) and duration of effects (3 months) was remarkably similar.

The drug had an excellent safety profile; patients reported only pain during injection and no systemic side effects.

CANNABINOIDS

The therapeutic potential of cannabinoids has been extensively investigated in chronic pain following the discovery of cannabinoidreceptors and their endogenous ligands.

Oromucosal cannabinoids (2.7 mg delta- 9-tetrahydrocannabinol/2.5 mg cannabidiol) are effective for multiple sclerosis associated pain and for refractory peripheral NP associated with allodynia.

Adverse events include dizziness, dry mouth, sedation, fatigue, gastrointestinal effects, and oral discomfort.

cannabinoids are not recommended for patients with psychiatric disorders.

There is controversy with regard to tolerance and dependence after long-term treatment.

STIMULATION TECHNIQUES ANDINTRATHECAL THERAPY

Transcutaneous electrical nerve stimulation (TENS) is commonly used for the treatment of pain associated with peripheral neuropathies, although the evidence level is moderate (Level B).

TENS can be proposed as a first-line treatment for painful focal neuropathies.

Interest in noninvasive brain stimulation (notably transcranial magnetic stimulation) for the treatment of NP is increasing.

Spinal cord stimulation has been reported to be efficacious in patients with failed back surgery syndrome , and motor cortex stimulation has been increasingly used for the treatment of peripheral or central painful neuropathic conditions.

For refractory NP, opioids and local anesthetics can be delivered intrathecally and have shown some benefit, although no Class I studies regarding their efficacy specifically in NP have been reported.

First Line Gabapentin Tricyclic antidepressants Tramadol Duloxetine Pregabalin

Second Line Lamotrigine Carbamazepine Bupropion SR Venlafaxine XR Opiate analgesics

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