(ĐTĐ) – Neuropathic pain can be very difficult to treat with only some 40-60% of patients achieving partial relief.
In addition to the work of Dworkin, O’Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy. These have combined evidence from randomized controlled trials with expert opinion.
Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.
It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as “antidepressants” and “anti-epileptic drugs” (AED’s). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.
Favored treatments are certain antidepressants e.g. tricyclics and selective serotonin-norepinephrine re-uptake inhibitors (SNRI’s), anticonvulsants, especially pregabalin (Lyrica) and gabapentin (Neurontin), and topical lidocaine. Opioid analgesics and tramadol are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive receptors, or desensitize C fibers such that they transmit fewer signals.
Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the painstem.
The functioning of antidepressants is different in neuropathic pain from that observed in depression. Activation of descending norepinephrinergic and serotonergic pathways to the spinal cord limit pain signals ascending to the pain. Antidepressants will relieve neuropathic pain in non-depressed persons.
In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.1516171819202122 Similarly, compounds that only block norepinephrine reuptake also do not improve neuropathic pain. Compounds such as duloxetine, venlafaxine, and milnacipran that block both serotonin reuptake and norepinephrine reuptake do improve neuropathic pain.
Bupropion has been found to have surprisingly high efficacy in the treatment of neuropathic pain.
Tricyclic antidepressants may also work on sodium channels in peripheral nerves.
Pregabalin (Lyrica) and gabapentin (Neurontin) work by blocking specific calcium channels on neurons. The actions of the anticonvulsants carbamazepine (Tegretol) and oxcarbazepine (Trileptal), especially effective on trigeminal neuralgia, are principally on sodium channels.
Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy in that subgroup on antiretroviral therapy.
Opioids, also known as narcotics, are increasingly recognized as important treatment options for chronic pain. They are not considered first line treatments in neuropathic pain but remain the most consistently effective class of drugs for this condition. Opioids must be used only in appropriate individuals and under close medical supervision.
Several opioids, particularly methadone have NMDA antagonist activity in addition to their µ-opioid agonist properties.
Methadone and ketobemidone possess NMDA antagonism. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of NMDA antagonism. It is reasonable to base the choice of opioid on other factors.
In some forms of neuropathy, especially post-herpetic neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.
Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers. Nevertheless, benefits appear to be modest.
Marijuana’s active ingredients are called cannabinoids. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult. Similar considerations apply to opioids.
A recent study showed smoked marijuana is beneficial in treating symptoms of HIV-associated peripheral neuropathy. Nabilone is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine.
The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use. A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.
Sativex, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain.
Long-term studies are needed to assess the probability of weight gain, unwanted psychological influences and other adverse effects.
Botulinum Toxin Type A (Botox, BTX-A)
Botulinum Toxin Type A (BTX-A) is best know by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration.
The utility of BTX-A in other painful conditions remains to be established.
The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by unacceptable side effects.
Reducing sympathetic nervous stimulation
In some neuropathic pain syndromes, “crosstalk” occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain.
Lesioning operations on the sympathetic panch of the autonomic nervous system are sometimes carried out.
There are two dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and benfotiamine.
A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy. While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia), the metanalysis showed “more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone”. There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.
Benfotiamine is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.
In addition to pharmacological treatment several other modalities are commonly recommended. While lacking adequate double blind trials, these have shown to reduce pain and improve patient quality of life for chronic neuropathic pain: chiropractic, yoga, massage, meditation, cognitive therapy, and prescribed exercise. Some pain management specialists will try acupuncture, with variable results.
Transcutaneous electrical nerve stimulation (TENS) may be worth considering in chronic neurogenic pain. TENS, with certain electrical waveforms, appears to have an acupuncture-like function.
Infrared photo therapy has been used to treat neuropathic symptoms. However, recent work has cast doubt on the value of this approach.
Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.
Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions for which they might be beneficial.
Spinal cord stimulators and implanted spinal pumps
Spinal cord stimulators, use electrodes placed adjacent to, but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or peakage. Lack of pain relief sometimes prompts device removal.
Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted.
There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time. These results must be viewed skeptically since placebo effects cannot be evaluated.
Motor cortex stimulation
Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal mempane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which requires a noticeable tingling (paresthesia) for benefit, the only palpable effect is pain relief.
Deep pain stimulation
The best long-term results with deep pain stimulation have been reported with targets in the periventricular/periaqueductal grey matter (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%). There is a significant complication rate which increase over time.
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