Neuropathic pain is a common cause of chronic pain and tends to be resistant to usual doses of traditional analgesic medications. Three classic examples of neuropathic pain include trigeminal neuralgia, PHN, and DN. Neuropathic pain is often described as lancinating or burning in nature. Both types of pain may be present at the same time, often accompanied by allodynia.
Neuropathic pain may be manageable with one or more adjuvant analgesic drugs, often prescribed as part of a comprehensive treatment plan. From a theoretical point of view, it may be helpful to categorize adjuvant analgesics into two broad classes of drugs, agents that act as membrane-stabilizing agents and drugs that enhance dorsal horn inhibition. Membrane-stabilizing drugs may act by blocking sodium and calcium channels on damaged neural membranes. Medications that enhance dorsal horn inhibition appear to act by augmenting spinal biogenic amine and GABAergic mechanisms. From a clinical standpoint, given the paucity of our understanding of neuropathic pain mechanisms and how the medications actually work, it is probably more useful to classify adjuvant drugs according to their traditional therapeutic indications (e.g., antidepressants and anticonvulsants). This point of view is strengthened by the fact that most drugs appear to have multiple mechanisms and sites of action, making further subclassification arbitrary and probably inaccurate.
Anticonvulsants, particularly carbamazepine (and more recently gabapentin and pregabalin), are useful for neuropathic pain. Although conventional wisdom suggests that anticonvulsants may be most effective for lancinating pain, anticon-vulsants are also useful for burning dysesthesias. The mechanism of action of gabapentin and pregabalin is poorly understood, but the drug has been demonstrated to bind to the alpha2delta subunits of the voltage-dependent calcium channel receptors (192). Gabapentin reduces the pain due to diabetic peripheral neuropathy and PHN; the overall safety record with gabapentin is good, making it an attractive alternative to carbamazepine and tricyclic antidepressants, particularly for elderly patients.
Clonazepam is another option and also poses minimal risk from the standpoint of organ toxicity. Clonazepam may be useful for radicular pain and pain associated with tumors, such as plexopathy. In addition, clonazepam may be used to supplement other adjuvant drugs. When given at bedtime, the mild sedating effect of clon-azepam can be helpful for patients who have difficulty sleeping because of pain.
Antidepressants have been used effectively for years in the management of multiple pain syndromes, including DN, PHN, rheumatoid arthritis, osteoarthritis, migraine headache, LBP, and fibromyalgia. However, pain relief is often modest and accompanied by side effects. Studies indicate that only one-third of patients obtain more than 50% pain reduction. However, some patients obtain dramatic pain relief.
The choice of which antidepressant to use for neuropathic pain often depends on the particular side effect profile of a given drug, because comparisons of individual tricyclic antidepressants have not shown great differences in efficacy. When a patient is having difficulty in sleeping because of pain, a more sedating drug, such as amitriptyline is appropriate. On the other hand, desipramine, which is considerably less sedating and has fewer anticholinergic effects, may be much better tolerated in elderly patients. Serotonin-selective reuptake inhibitors for neuropathic pain have been disappointing, although paroxetine at relatively high doses is useful for DN. Fluoxetine may be useful in the treatment of rheumatic pain conditions, many of which have neuropathic components. As with the tricyclic agents, the SSRIs are probably interchangeable. However, SSRIs are better tolerated than tricyclics and may be extremely effective in treating patients with chronic pain and concomitant depression.
It remains unclear whether anticonvulsants or antidepressants should be first-line therapy for neuropathic pain. Similar results have been obtained with both, and current evidence concerning drug efficacy does not support the use of one drug over another. In many cases, selection of a particular drug may depend more on expected side effects (e.g., sedation) or the clinician's experience with the drug, than theoretical considerations about mechanisms of drug action. It must be remembered that treatment of neuropathic pain remains largely empirical. In addition, for maximum analgesic benefit, more than one drug may be necessary. Until more effective medications become available, polypharmacy will remain the rule instead of the exception. This is probably understandable, given the multiple mechanisms involved in the pathophysiology of neuropathic pain.
In general, for neuropathic pain either gabapentin or amitriptyline (or a similar tricyclic antidepressant) should be first-line therapy. When considering issues such as time to effective analgesic action and toxicity, gabapentin is more attractive. Gabapentin often is our first choice, followed by a tricyclic antidepressant, such as nortriptyline. Both drugs must be started slowly and titrated to effect, perhaps to rather high levels, for full benefit. However, tricyclics have many potential side effects that must be considered, particularly anticholinergic and cardiac interactions and organ toxicity. Clearly, gabapentin is a safer drug, but may cause sedation or dysphoria in some patients. Occasionally patients complain of weight gain and nonpitting edema. Until recently another disadvantages of gabapentin included its cost (approximately 10 times the cost of a generic tricyclic antidepressant at usual starting doses) and the need to take the drug three or four times a day. Keep in mind that the dosage of gabapentin must be reduced appropriately for patients with renal insufficiency. Newer marketed medications such as duloxetine and pregabalin may also, as time and treatment experience grows, become primary treatments.
An evidence-based treatment algorithm for neuropathic pain treatment was performed and identified 105 RCTs using MEDLINE and EMBASE. The tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were found to be the most frequently studied. In the treatment of neuropathic pain, the lowest number needed to treat (NNT) was for the TCAs, followed by the opiates, and then the anticonvulsants gabapentin and pregabalin. It was felt that the NNT along with the NNH (number needed to harm) were the best way to assess relative efficacy between trails, but they have significant limitations (321).
When an appropriate medication trial has been ineffective, and all other appropriate medications have been tried and failed or delivered minimal effectiveness, an interdisciplinary pain medicine approach should be considered (see Chapter 17). Reducing dependence on opioid medications may or may not be a primary goal, depending on whether the pain syndrome is opioid responsive, the patient is demonstrating appropriate improvements in function, and there are not undue side effects or evidence of drug abuse.
Current evidence indicates that nonpharmacological approaches may be reasonable, obviate or reduce the need for potentially toxic medications, and improve the effectiveness of analgesic regimens. Spinal cord stimulation may reduce pain in selected patients. Less invasive techniques, including TENS units and percutaneous nerve stimulation, are also beneficial.
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