© American Academy of Pain Medicine 2015
Timothy R. Deer, Michael S. Leong and Vitaly Gordin (eds.)Treatment of Chronic Pain by Medical Approaches10.1007/978-1-4939-1818-8_55. Anticonvulsant Medications for Treatment of Neuropathic and “Functional” Pain
(1)
Division of Pain Medicine, Department of Anesthesiology, Lehigh Valley Health Network, 1240 South Cedar Crest BLVD, Suite 307, Allentown, PA 18103, USA
Key Points
Anticonvulsant therapy is effective for the treatment of neuropathic pain.
Efficacy is well demonstrated in selected neuropathic pain syndromes.
Little evidence is available to support generalized use in treatment of neuropathic pain.
Further research is required to evaluate the utility of anticonvulsant therapy in combination with other drugs.
Introduction
The broad definition of neuropathic pain as articulated by the International Association of Pain, “pain initiated or caused by a primary lesion or dysfunction of the nervous system,” unfortunately has done little to guide the clinician when attempting to develop an effective treatment plan that may include an anticonvulsant medication. Current guidelines and indications for use of anticonvulsant therapy primarily utilize a lesion-based approach when recommending treatment for patients suffering from neuropathic pain. However, recent work by Baron and colleagues would suggest that selection of patients based on sensory symptoms and signs rather than strictly by disease etiology has potential benefits in identifying successful therapeutic outcomes [1].
Initial use of anticonvulsant drugs for the etiologic-based treatment of neuropathic pain dates back almost 50 years, with the sequential trials of carbamazepine for the treatment of trigeminal neuralgia [2–4]. From the mid-1960s until the mid-1990s, only a limited number of clinical trials utilizing anticonvulsants had been completed for the treatment of neuropathic pain. Subsequent to the introduction of gabapentin for the treatment of epilepsy in the mid-1990s, case reports of successful treatment of neuropathic pain began to appear in the medical literature [5, 6]. Several recent reviews of the literature along with meta-analysis of randomized controlled trials (RCT) now support the use of anticonvulsant therapy for first-line treatment of selected neuropathic pain syndromes [7–9]. More recently, fibromyalgia (functional pain) now widely considered to be a neuropathic pain syndrome manifested by widespread pain due to underlying changes in sensory processing has been effectively treated with anticonvulsant therapy [3].
The body of evidence supporting the use of anticonvulsant therapy for the treatment of neuropathic pain as a generalized category is rather limited. The vast majority of clinical trials involving anticonvulsant drugs have been narrowly focused on treatment of specific conditions such as painful peripheral diabetic neuropathy and postherpetic neuralgia [8, 10, 11]. To date, only one trial has been published supporting the use of anticonvulsant therapy for the treatment of neuropathic cancer pain [12]. Of considerable interest is that the literature is devoid of a single trial demonstrating efficacy of anticonvulsant therapy in one of the most common forms of neuropathic pain that being neuropathic low back pain. The following review of anticonvulsant drugs will focus on clinically relevant aspects for the practicing clinician.
Carbamazepine and Oxcarbazepine
Few neuropathic pain conditions are more effectively managed with anticonvulsant therapy than classic trigeminal neuralgia [13, 14]. Consensus guidelines remain clear that carbamazepine is the drug of first choice with initial efficacy of upwards to 80 % and long-term efficacy of 50 % at doses between 200 and 400 mg administered three times a day [14]. Carbamazepine exerts a use-dependent inhibition of sodium channels that leads to a reduction in the frequency of sustained repetitive firing of action potentials in neurons. The effect on pain suppression is hypothesized to occur through both central and peripheral mechanisms. Carbamazepine use in three placebo-controlled studies for treatment trigeminal neuralgia demonstrated a combined numbers needed to treat (NNT) for effectiveness of 1.7 [15].
In a single 2-week placebo-controlled trial involving only 30 participants, carbamazepine demonstrated an NNT of 2.3 for treatment of painful diabetic neuropathy (PDN) [16]. However, several other clinical trials involving various neuropathic pain conditions that include PDN and postherpetic neuralgia (PHN) have failed to demonstrate clinical benefit measured by improvement in pain scores [10].
Unfortunately, problematic issues that may significantly limit the use as well as long-term efficacy include hepatic enzyme induction effects of carbamazepine. This particularly vexing side effect frequently requires close monitoring of other drug activity such as warfarin. Ongoing monitoring of liver function and blood count is recommended as well. The second-generation anticonvulsant oxcarbazepine has a structurally similar sodium channel inhibitor effect as carbamazepine but with significantly fewer complicating side effects. In two relatively small randomized controlled trials, oxcarbazepine was found to be similar to carbamazepine in reduction of number of attacks in patients suffering with trigeminal neuralgia [14]. Titration dosing from 300 mg QD to maximum of 900 mg BID over 5 days is recommended in order to minimize side effects such as dizziness and sedation. One concerning serious side effect is hyponatremia, which may occur in approximately 3 % of individuals taking oxcarbazepine; therefore, monitoring of sodium levels is recommended [10, 15].
Gabapentin and Pregabalin
Gabapentin original synthesized in 1977 as a drug for the treatment of spasticity and subsequently introduced in the mid-1990s for the treatment of epilepsy has garnered over 3,200 citations in the medical literature, with over 1,200 citations in the area of pain [17]. Since 1995, gabapentin has gained approval for the treatment of postherpetic neuralgia in the USA and for the broader indication of peripheral neuropathic pain in many countries outside of the United States [18]. In 2003, a second-generation alpha-2-delta-binding drug pregabalin was introduced in the United States, and FDA approved it for the treatment of epilepsy, postherpetic neuralgia, and painful diabetic peripheral neuropathy and more recently for the treatment of fibromyalgia [19, 20].
Whereas gabapentin and pregabalin both bind to the presynaptic neuronal alpha-2-delta subunit of voltage-gated calcium channels, pregabalin’s unique chemical structure confers several clinically important features that distinguish it from gabapentin. Both drugs share the similar characteristics when binding to the alpha-2-delta subunit of voltage-gated calcium channels which results in decreased expression and release of certain neurotransmitters that include substance P, glutamate, and calcitonin-related gene peptide all of which are considered important for induction and maintenance of neuropathic pain states. The suppression of the above-mentioned neuronal peptide activity occurs primarily after tissue or nerve injury has occurred. This unique upregulation of the alpha-2-delta subunit on voltage-gated calcium channels is thought to be required for drug activity, as there is minimal drug effect on activity of normal nerve transmission [21, 22].
Pharmacokinetic characteristic particular to pregabalin that may have clinical benefit over gabapentin includes the linear absorption of pregabalin, which increases proportionally with each dose, resulting in a uniformly linear dose-exposure response across patient populations. On the other hand, the pharmacokinetic profile of gabapentin is considered nonlinear, and bioavailability (approximately 60 % at a dose of 900 mg) is significantly lower and less predictable across patient populations. The amount of gabapentin absorbed is dose dependent, with the proportion of drug absorbed decreasing with increasing dose to the point where only a fraction of the dose is absorbed at relatively higher doses. In single-dose absorption studies, the amount of gabapentin absorbed decreases from 80 % at 100 mg to 27 % at 1,600 mg [18]. On the contrary, pregabalin absorption is independent of dose administered; it is constant and averages >90 % over the dose range of 10–300 mg in single-dose trials [19]. Consequently, this particular pharmacokinetic difference translates into minimal variations between patients in plasma concentrations for pregabalin with dose titration. Whether this has any clinically important, significance remains to be determined, as this has not been measured in any head-to-head trials between gabapentin and pregabalin.
Clinically important characteristics of both gabapentin and pregabalin that simplify the use of these drugs include minimal protein binding and minimal or little drug-drug interaction which importantly includes warfarin. As well, favorable elimination characteristics include minimal metabolism and no CYP 450 interaction for both gabapentin and pregabalin, allowing the clinician to prescribe either drug in a patient who may be taking multiple other medications that may be affected by hepatic enzyme induction. It is particularly important to note clinically that gabapentin and pregabalin do not have any effect on renal function, as quite often this is a misunderstood concept that results in the withdrawal of therapy in patients with renal impairment. However, it is important to take into consideration when dosing both drugs that approximately 95 % of ingested gabapentin and pregabalin is eliminated, unchanged through renal excretion. Therefore, with decreasing creatinine clearance (CC), the dose of drug administered may be decreased proportionally from full-recommended dosing levels when CC is above 60–30 % or less of the normal dose when CC is below 30 [18, 19].
Gabapentin Therapy
Fourteen studies detailing use of gabapentin included the following conditions: two studies in postherpetic neuralgia (PHN), seven studies in painful diabetic neuropathy (PDN), and one each in cancer related neuropathic pain, phantom limb pain, Guillain-Barré syndrome, spinal cord injury pain, and mixed neuropathic pain states [12, 17, 23, 24]. In 2002, gabapentin was the first medication to be granted FDA approval for the treatment of postherpetic neuralgia. RCT results demonstrated in 336 PHN patients that dosing between 1,800 and 3,600 mg/day resulted in a 33–35 % reduction in pain compared to a 7.7 % pain score reduction in the placebo group. Overall, 43.2 % of subjects treated with gabapentin categorized their pain as “much” or “moderately” improved at the end of the study, whereas only 12.1 % in the placebo group experienced any significant improvement [25]. Three trials considered of fair quality conducted over 6–8-week duration at dosing levels varying between 900 and 3,600 mg/day demonstrated mixed results in the same condition [9, 17]. The Cochrane database analysis supports the use of gabapentin for treatment of chronic neuropathic pain and suggests that the numbers needed to treat (NNT) for improvement in all trials with evaluable data is around 5.1. Clinically, it is important to understand that on average, only one in approximately every five patients who receive gabapentin for the treatment of neuropathic pain will report significant improvement [11].
Of clinical importance are the adverse events that occurred more frequently in the gabapentin group compared to those in receiving placebo in decreasing order included somnolence, dizziness, and peripheral edema. The former-mentioned side effect of somnolence may be clinically beneficial in patients suffering from sleep deprivation due to neuropathic pain. The usual starting dose of gabapentin may vary depending on patient tolerance to pharmacotherapy. Therefore, one may start at a very low dose of 100 mg TID of QID titrating to efficacy that is usually seen at an average total daily dose between 900 and 1,800 mg, with occasional dosing to 2,400 mg/day. As mentioned above, asymmetric dosing of gabapentin giving a larger dose of drug at bedtime (600–1,200 mg) to induce somnolence and a lower dose in the morning (300–600 mg) and afternoon (300–600 mg) may help mitigate the somnolence and dizziness side effect profile during the waking hours while improving the sleep-related comorbidity found in up to 80 % of patients suffering with chronic neuropathic pain [9, 26, 27].
Pregabalin Therapy
Pregabalin, a second-generation alpha-2-delta analogue, has demonstrated efficacy in the treatment of postherpetic neuralgia, painful diabetic neuropathy, and central neuropathic pain. In general, the 19 published clinical trials have demonstrated that total daily doses of 150, 300, 450, and 600 mg daily were effective in patients suffering with neuropathic pain. The NNT for at least 50 % pain relief at 600 mg daily dosing compared with placebo were 3.9 for postherpetic neuralgia in five studies, 5.0 for painful diabetic neuropathy in seven studies, and 5.6 for central neuropathic pain in two studies [8, 10, 11, 16].
Seven randomized controlled trials were completed, evaluating the efficacy of pregabalin for treatment of painful diabetic neuropathy (PDN). Dosing ranged between 150 mg/day and a maximum of 600 mg/day with duration of treatment varying from 5 to 13 weeks. Average onset to significant improvement in pain was somewhat related to dosing being 4 days at 600 mg/day and 5 days at 300 mg/day. The longest onset to pain relief occurred in the 150 mg/day treatment group occurring as long as 13 days after start of drug. Analysis of the various dosing schedules for the PDN trials revealed that TID dosing was effective at 150–450 mg/day; however, efficacy in BID dosing was only seen at a total daily dose of 600 mg/day (300 mg BID). Although efficacy was demonstrated across a dosing range of 150–600 mg/day, FDA approval is for total daily dosing of 150–300 mg divided and given TID [28–30].
Three randomized controlled trials varying between 8 and 13 weeks in duration have looked at the efficacy of pregabalin for the treatment of postherpetic neuralgia. Consistent improvement across all three trials was found at dosing strengths between 150 and 600 mg/day. The dosing interval of BID or TID did not seem to affect patient responses at any total dose between 150 and 600 mg/day [20, 31, 32]. Of clinical interest was the varying response in overall pain relief that was targeted at 50 % improvement, but varied depending on the study between 20 and 50 % for the participants.
Two clinical trials involving over 300 patients with central pain found that relatively high doses of pregabalin 600 mg/day were required to achieve even results of minor significance. NNT for 35 % improvement were around 3.5 (2.3–7) and for 50 % improvement around 5.6 (3.5–14), while the discontinuation rates due to lack of efficacy and side effects (all minor) were somewhere around 50 % of participants [8, 11].
Of clinical importance is that consistent across all neuropathic pain trials regardless of condition treated, there was a generalized tendency towards greater improvement in pain relief with increasing dose of drug to a maximum of 600 mg/day. In addition, when compared to placebo on several of the SF-36 subscales, pregabalin demonstrated general improvement [33]. As with gabapentin, the beneficial effect on sleep has been demonstrated with pregabalin therapy in patients suffering with neuropathic pain [31, 34].
In conclusion, when looking at the pregabalin clinical trial data, substantially greater benefit was found at doses between 300 and 600 mg/day administered either BID or TID for the treatment of postherpetic neuralgia and painful diabetic neuropathy and with less but still clinically relevant benefit in central neuropathic pain [33]. Regardless of the pregabalin dose, only a minority of patients will have attained substantial benefit with pregabalin >50 %; however, the majority will demonstrate moderate benefit of between 30 and 50 % reduction in pain [9, 11, 16].
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