Chronic Pain & Neuroplasticity -> Neurovascularplasticity
Nociceptive pain is defined as pain resulting from activation of the normal nociceptive pathways. It can occur with inflammatory processes. Neuropathic pain is defined as pain initiated or caused by a primary lesion, or dysfunction in the peripheral or central nervous system. Patients with neuropathic pain often complain of spontaneous and/or evoked pain. Spontaneous components include lancinating pain (usually electric-like and paroxysmal), burning pain (typically constant and superficial), and cramping/aching pain (usually deep and commonly musculoskeletal). Evoked pain components include hyperalgesia, allodynia, and hyperpathia. Chronic pain can be neuropathic in origin, nociceptive, or mixed.
Causes of Neuropathic Pain: Traumas: Improper healing that involves peripheral/central sensitization/excitability. Metabolic: includes conditions such as diabetic neuropathy, alcoholic neuropathy, uremic neuropathy, and other nutritional neuropathies. Ischemic: Toxic or drug induced: includes poisoning from substances such as arsenic and thalium, and drugs such as isoniazid, nitrofurantonin, vincristine, and cisplatinum. Paraneoplastic: (ex) small-cell carcinomas sensory neuropathies. Hereditary: (ex) sensory neuropathy type I. Immune: Infectious/postinfectious: (ex) acute zoster, post-herpetic neuralgia and HIV related neuropathies. Miscellaneous :
Neuropathic Pain has peripheral as well as central origins. Peripherally, increased sensitization of nociceptors to external mechanical and thermal stimuli (peripheral hypersensitivity) is a contributing factor. Injured C-fiber nociceptors can develop new adrenergic receptors and sensitivity, which contribute toward sympathetically maintained pain. Ectopic (abnormal) discharges from lesional sites in primary afferent neurons are contributory and may be explained by an upregulation or dysfunction of sodium channels. In addition, plasma, immune cells, and afferent fibers are involved in the neurogenic inflammation process (vasodilation, plasma protein extravasation, release of vasoactive peptides), which leads to the release of varied neurotransmitters, resulting in chemosensitivity. Neurogenic inflammation in dura matter may serve as a possible pathomechanism , underlying vascular head pain. Overall, the peripheral mechanisms of pain are complex.
Some mechanisms resulting in peripheral sensitization have been well-documented. Following a peripheral nerve injury, an inflammatory reaction occurs with the release of a variety of neurotransmitters, referred to as a sensitizing "soup". These substances are released from damaged and inflammatory cells, including macrophages, mast cells, and lymphocytes. In addition, nociceptive stimulation causes a neurogenic inflammatory response with the release of norepinephrine (NE), serotonin (5-HT), SP (substance P / NK-1 receptors), neurokinin A, and calcitonin gene-related peptide from the nociceptive afferent fibers. This inflammatory reaction results in a decreased threshold of nociceptors. In addition, there is an abnormal expression and accumulation of sodium channels (NA+ channels) at the A and C nociceptors at the level of injury, which partially accounts for the ectopic discharges following peripheral sensitization. The peripheral afferent nociceptors may, therefore, become overly sensitive to mechanical and/or thermal stimuli. Since peripheral injury is partially related to an accumulation of sodium channels, some argue the best way to treat peripheral sensitization is via agents that modulate sodium (Na+) channels rather than or in addition to the sensitizing soup.
The process of central sensitization starts early in deafferentation. Following peripheral nerve injury, the peripheral nociceptor fibers release excitatory neurotransmitters, particularly glutamate and aspartate, both of which are excitatory in nature. These excitatory neurotransmitters activate a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, which cause calcium influx from voltage-gated Ca++ channels. Neurokinins and substance P interact with the NK-1 receptors, also leading to calcium entry. Activating these receptors removes the magnesium plug from the NMDA receptors, allowing more calcium entry into the cell. Calcium then acts as an important secondary messenger. It activates nitric oxide, leads to immediate early gene expression, and phosphorylates numerous receptors at the level of the dorsal horn, including the NMDA receptors, leading to a decreased threshold of the dorsal horn neurons and to ectopic discharges. This phenomenon is referred to as central sensitization. The pathophysiologic changes suggest that modulation of central sensitization can be accomplished by NMDA-blocking agents, NK-1 receptor blocking agents, or with high-voltage calcium channel modulators.
In summary, we reviewed the pathophysiology of neuropathic pain and the evidence of efficacy derived from randomized clinical trials. Agents demonstrating efficacy which we discussed include TCAs, SSNRIs, tramadol, opiates, carbamazepine (CBZ), oxcarbazepine (OXC), topiramate (TPM), lidocaine, gabapentin (GBP), capsaicin, and levodopa. Because many patients with painful neuropathies require polytherapy, it is important to combine drugs that modulate different pathways to maximize the likelihood of adequate pain relief. Research on the mechanisms of the agents discussed, as well as future agents, will continue to be researched.
While NK-1(substance P) receptor blockers have been developed there are no currently marketed drugs which have a primary action as an NK-1/SP blocker. It is involved in peripheral & central sensitization as well as descending inhibition from the brain and will likely be added to the mechanistic approach when these agents become available.
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Some off patent drugs like clonidine & patent protected drugs like tizanidine & 5HT3 (serotonin-3 receptor) antagonist ondansetron have some inhibitory effects on the release of substance P. Other alpha2 & current antidepressant drugs may also have indirect effects on the release of substance P.
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Note: Alpha 2-agonistic agents interact with TCAs (Tricyclic anitdepressants) generally requiring a higher dose of them for the same effect. Mirtazapine tetracyclic antidepressant (alpha 2 hetero/auto receptor antagonist) could block alpha 2-agonists entirely but may have other SP antagonism via its 5HT3 & other pharmacological properties. Venlafaxine seems to potentiate the effects of clonidine.
As depicted in the last slide above there are many currently available proven treatments for neuropathic pain. Here is a more comprehensive list of treatments:
Pharmacologic Management of Neuropathic Pain: Antidepressants (older TCAs are proven Na+ channel (possibly also NMDA) modulators in addition to their NE/5HT (norepinephrine/serotonin) modulation and usually work within 1-3 weeks but are generally harder to tolerate)- amitriptyline, imipramine, desipramine, nortriptyline, (SSNRI)-venlafaxine, (NaSSA)- mirtazapine (anecdotal reports with certain chronic pain), (SSRIs) - less well established. Anticonvulsants - Carbamazepine, oxcarbazepine, clonazepam, gabapentin, lamotrigine, phenytoin, valproic acid, topiramate. Antiarrhythmics-mexiletine. Topical formuations- Capsaicin, lidocaine, ketamine, clonidine, guanethidine, gabapentin, Doxepin & other TCAs, aspirin (NSAIDs)*. Others- Tramadol, Baclofen, levodopa, pimozide, corticosteroids, NMDA antagonists (ketamine, dextromethorphan, amantadine, memantine from Germany, future antidepressants), clonidine, opioids (methadone, dextropropoxyphene, ketobemidone are also NMDA antagonists which may impact tolerance to opioid analgesics in neuropathic pain; some reports that if a CCK antagonist is administered, then opiate sensitivity in neuropathic pain may return), intrathecal pumps. Non-pharm: Spinal cord stimulator (thought in part a GABAergic mechanism), ECT (thought through in part Ca++), invasive/surgical procedures. Diet & CAM (Complimentary Alternative Medicine- SJW, SAM-e, etc)
* Compounded Topical Formulation Examples: (Transdermal creams/lotions or PLO gels) Neuropathy - Ketamine 10%/Gabapentin 6%/Clonidine 0.2% ; Diabetic Peripheral Neuropathy - Ketoprofen 10%/Amitriptyline 2%/Carbamazepine 2% ; Fibromyalgia - Ketoprofen 10%/Baclofen 5%/Lidocaine 5% ; Neuropathy/Allodynia - Ketamine - 10%/Gabapentin 6%/Clonidine 0.2% or (Topical Spray) - Ketamine 5%/Lidocaine 8%/Bupivacaine 2% ; Complex Regional Pain Syndrome - Guanethidine 2%/Lidocaine 5%/Ketamine 5% (Topical Spray) ; others: capsaicin 0.025%-high potency, Flurbiprofen 5%. If systemic side effects from oral administration are not tolerated than transdermal formulations may be worth a trial since they do make systemic events much less common (& pain modulating receptors are found in the skin) but sensitive skin conditions will have to experiment with finding a vehicle and formulation that doesn't irritate their underlying condition more than its beneficial effects.
Assessment of the Neuropathy: Noninvasive: QST, EMG, autonomic function tests Invasive: Cutaneous/nerve biopsy. It is proposed that quantitative sensory tests (QST), skin blood flow, and skin biopsies measuring nerve fibers positive for protein gene product 9.5 are better suited to evaluate C fibers for level of function and recovery-Medscape (requires free sign-up).
Symptomatic Treatment of Painful Neuropathies: Treatment recommendations: - It is essential to start a given medication at a low dose, and gradually titrate to efficacy. - If a patient experiences partial pain relief with 1 drug as monotherapy, a combination of 2 or more drugs with complimentary mechanisms can often yield better results in terms of efficacy. - In general, when a patient remains pain-free for 3 months on a current treatment regimen, consideration to a slow taper should be given.
Approach to Neuropathic Pain: No consensus exists on the best approach for treating neuropathic pain. One approach is to treat the pain according to the underlying condition. Although treatment according to the underlying medical condition is an attractive approach indeed, it is not easily converted into clinical practice. This is largely because most clinical trials evaluating the safety and efficacy of various agents in the treatment of neuropathic pain were conducted for only 3 conditions: painful diabetic neuropathy, trigeminal neuralgia, and post-herpetic neuralgia. Physicians have extrapolated results from these trials and applied them to patients with other painful neuropathies. Although this usually works, it is not always the most successful approach.
Another approach is to treat the pain according to the pain characteristics. For instance, TCAs, oral local anesthetics, or alpha-2 agonists may be recommended for treating burning or aching pain, whereas anticonvulsants and y-aminobutyric acid (GABA) may be effective for lancinating or stabbing components. Although this approach is conceptually attractive, it did not hold up in clinical trials because drugs that are effective are usually efficacious against multiple pain components.
Another approach is to treat neuropathic pain according to the maladaptive pathophysiologic changes occurring after deafferentation that initiate and maintain the pain (mechanistic approach). This approach requires a thorough understanding of the pathophysiology of neuropathic pain and a knowledge of the mechanisms of actions of the various drugs and therapies available for treating the conditions.
There is a shift toward a mechanistic approach based on the following: - Other approaches are difficult to translate into clinical practice. - There are several different pain components, many of which are similar across various conditions. - Increased understanding of the maladaptive pathophysiologic changes occurring after deafferentation (changes that initiate and maintain pain). - Increased knowledge of the mechanisms of action of antineuralgic agents.
These chronic pain and their neurovascularplasticity principles discusssed here could apply to the understanding & treatments of neurovascular conditions like rosacea, inflammatory keratosis pilaris, erythromelalgia (EM), raynauds phenomenon, facial neuralgias, headache syndromes, complex regional pain (RSD & causalgia).
Implications for vascular laser & IPL treatments - If a chronic or neuropathic pain condition exists it makes sense to have it addressed before beginning photothermolysis (i.e. discuss with your pain specialist) so as not to have it contribute toward any potential sensitization.
http://www.pain.com - Find a pain clinic/specialist in your area & much more.
Pain News & Information - Pain Treatment Updates at helpforpain.com
Pain, The Disease - More on pain underscoring the idea that chronic pain is a disease in itself that needs to be treated, preferably with early recognition & intervention.
International Association for the Study of Pain - Website Subject Index
* Caveat: Full PowerPoint presentations designed for medical professionals* (only overview slides have no elaboration-discuss with your doctors) below were prepared with an unaffiliated, unrestricted educational grant by the makers of oxcarbazepine, a keto-analog of carbamazepine. While the mechanisms covered appear fairly well-balanced the overall push seems to be for oxcarbazepine (perhaps in part since it is still under patent protection). In general it is reported to be better tolerated (no black box warning) than carbamazepine with comparable efficacy but costs substantially more than its much older marketed analog. For non-malignant facial flushing associated pain however first-line drugs based on current available studies and some anecdotal reports would likely be in the immediate term (usually works within hours) clonidine (reduces SNS activity & release of substance P) & possibly clonazepam (reduces ectopic discharges) with venlafaxine (or TCAs or possibly mirtazapine) & gabapentin as longer term agents (usually works within days to weeks). Other agents above would likely be considered second-line drugs depending on diagnosis. Despite all the clinical trials and classes of drugs discussed, the only drugs currently approved by the FDA for the treatment of neuropathic pain are carbamazepine (for trigeminal neuralgia) and lidocaine (post-herpetic neuralgia). As these can be powerful modulating drugs and treatments with diverse effects, consideration of any diagnosis and treatment (label & off-label) for chronic pain should be discussed with your doctors with continual risk:benefit ratio analysis.
* Requires Microsoft PowerPoint or free viewer (just use arrow keys or spacebar/backspace keys to navigate through slides & Esc key to end) available for download & install below:
Microsoft PowerPoint Viewer 97 - Downloads - CNET.com
or at Microsoft below:
Downloads for PowerPoint Users or Microsoft Office - PowerPoint Home Page
(Right-click to Save Target)
Core Presentation - Mechanistic Approach to Neuropathic Pain - Expanding the Role of Antiepileptics * (868KB)
Clinical Issues (this one loops so hit Esc key at end) (95KB)
Case Studies (80KB)
Treatment Survey (391KB)
Survey is a reflection of some current treatment preferences of a large number of physicians with expertise in the management of pain, and it should not be construed as a treatment algorithm without objective evidence derived from clinical trials to support each choice. It is hoped that physicians will consider the pathophysiologic changes resulting in pain, as well as the antineuralgic mechanism of action of the various agents. Such an approach will hopefully lead to the rational selection of drugs as monotherapy, but especially in combination therapy, with the aim of improving the patients well-being.
* Aside from Neuropathic Pain, Antiepileptics/Anticonvulsants are increasingly being used for anxiety disorders & mood stabilization. Depression, anxiety, flushing, pain & seizures share neural circuitry (although one does not necessitate another). The precise mechanisms of each are being investigated daily.
Warnings: The information above is provided for educational purposes and may not be construed as a medical prescription or as a substitute for the advice of your physicians.
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