Adjuvant Analgesics for Persistent (Chronic) Neuropathic Pain

Chapter 23


Adjuvant Analgesics for Persistent (Chronic) Neuropathic Pain



SOME of the adjuvant analgesic classes are conventionally used solely for persistent neuropathic pain. The drugs in these classes, combined with the drugs in classes subsumed under the category of multipurpose analgesics, offer a very large group of individual agents that might be useful for pains of this type. Antidepressants and anticonvulsants are the first-line adjuvant analgesics for a wide variety of neuropathic pain syndromes. The multipurpose antidepressants were discussed earlier in Chapter 22, and the anticonvulsants will be discussed in detail here. Refractory neuropathic pain, which has not responded to these first-line approaches, may be considered for trials of the other so-called multipurpose drugs, or other agents classified as drugs used conventionally for neuropathic pain. Other adjuvant agents used for refractory neuropathic pain include sodium channel blockers, several topical agents, gamma aminobutyric acid (GABA) agonists (baclofen [Lioresal]), N-methyl-d-aspartate (NMDA) receptor antagonists (e.g., dextromethorphan and ketamine), and the relatively new intrathecal drug, ziconotide (Prialt). In addition to persistent pain, certain adjuvant agents are used to manage the neuropathic component of some types of acute pain and for the purpose of preventing persistent neuropathic pain, such as persistent neuropathic postsurgical pain. These are discussed later in this section.


Recent systematic reviews, some with evidence-based guidelines for drug selection, provide information about a range of therapies used for neuropathic pain (Finnerup, Otto, McQuay, et al., 2005; Saarto, Wiffen, 2007; Kroenke, Krebs, Bair, 2009). Table 23-1 lists many of these drugs, and Table V-1 at the end of Section V provides dosing guidelines and other characteristics of many of the adjuvant analgesics for the treatment of neuropathic pain. See also Section II for assessment of neuropathic pain.



Guidelines





Anticonvulsant Drugs


Several systematic reviews of randomized controlled trials of anticonvulsants for pain management have demonstrated strong evidence to support the efficacy of anticonvulsants in the management of both acute and persistent neuropathic pain (Backonja, Glanzman, 2003; Backonja, Serra, 2004; Goodyear-Smith, Halliwell, 2009; Serpell, Neuropathic Pain Study Group, 2002; Wiffen, Collins, McQuay, et al., 2005; Wiffen, McQuay, Rees, et al., 2005; Wiffen, McQuay, Moore, 2005). They are listed as first-line agents in several evidence-based neuropathic pain treatment guidelines (Argoff, Backonja, Belgrade, et al., 2006; Dworkin, Backonja, Rowbotham, et al., 2003; Dworkin, O’Connor, Backonja, et al., 2007; Moulin, Clark, Gilron, et al., 2007). There is good evidence to support the clinical impression that anticonvulsants may be effective for all qualities of neuropathic pain, including neuropathic pain that does not have a dysesthetic component, neuropathic pain described as continuous dysesthesia (e.g., burning), and neuropathic pain that is lancinating, sharp, shooting, stabbing, or knifelike (Backonja, Glanzman, 2003; Krafft, 2008; Serpell, Neuropathic Pain Study Group, 2002; Wiffen, McQuay, Rees, et al., 2005; Wiffen, McQuay, Moore, 2005).


Anticonvulsants are discussed today in terms of the length of time they have been available (Gilron, 2006). The “older” or “first-generation” anticonvulsants include carbamazepine (Tegretol), phenytoin (Dilantin), clonazepam (Klonopin), divalproex sodium (Depakote), and valproic acid or valproate (Depacon, Depakene). Anticonvulsants that are referred to as “newer” or “second-generation” include the alpha-2-delta-1 modulators gabapentin (Neurontin) and pregabalin (Lyrica), lamotrigine (Lamictal), oxcarbazepine (Trileptal), tiagabine (Gabitril), topiramate (Topamax), zonisamide (Zonegran), lacosamide (Vimpat), and felbamate (Felbatol). One group of researchers commented that the quality of research, and hence of the evidence, tends to be higher with the newer anticonvulsants (Goodyear-Smith, Halliwell, 2009). With the exception of felbamate, which has the potential for serious bone marrow toxicity, the newer anticonvulsants generally have better safety profiles and now are prescribed as the first-line drugs for epilepsy and neuropathic pain.



“Newer” Second-Generation Anticonvulsants


Following is a discussion of several of the “newer” second-generation anticonvulsants. See Chapter 26 for their use in acute pain treatment.



Gabapentin


Gabapentin (Neurontin) has been demonstrated to be analgesic in many types of neuropathic pain, some other types of persistent pain, and acute perioperative pain (Knotkova, Pappagallo, 2007; Kong, Irwin, 2007; Seib, Paul, 2006; Tiippana, Hamunen, Kontinen, et al., 2007; Wiffen, McQuay, Rees, et al., 2005). (See Chapter 26 for perioperative use of gabapentin.) For example, a large randomized, placebo-controlled study of 305 patients with diverse neuropathic pain syndromes, including postherpetic neuralgia, complex regional pain syndrome (CRPS), central pain, and persistent postsurgical pain, found that gabapentin in doses up to 2400 mg were well-tolerated and improved pain intensity by 21% compared with 14% with placebo (Serpell, Neuropathic Pain Study Group, 2002). Improvements were noted in patient-reported quality of life and functional indicators as well.


Other studies confirmed the potential utility of gabapentin in specific syndromes. A large, multicenter 7-week study randomized 334 patients with postherpetic neuralgia to receive 1800 or 2400 mg of gabapentin or placebo daily in three divided doses (Rice, Maton, Postherpetic Neuralgia Study Group, 2001). Within 1 week, pain scores were reduced, with a final improvement difference from baseline pain of approximately 34.5% for the 1800 mg dose and 34.4% for the 2400 mg dose. The drug was well-tolerated, with the worst adverse effects being dizziness and sedation, which were especially bothersome during the titration phase. Additional studies in the population with postherpetic neuralgia observed similar results (Backonja, Glanzman, 2003).


Guidelines recommend gabapentin as a first-line (Dworkin, O’Connor, Backonja, et al., 2007) or second-line (Argoff, Backonja, Belgrade, et al., 2006) analgesic for treatment of painful diabetic neuropathy. A 12-week open-label pilot study of 25 patients with type-II diabetes and neuropathy demonstrated greater pain reduction, decreased paresthesia, and less frequent adverse effects with gabapentin than with amitriptyline (Elavil) (Dallocchio, Buffa, Mazzarello, et al., 2000). Other studies in this condition have confirmed these positive results (Backonja, Glanzman 2003).


A randomized controlled trial evaluated gabapentin for the treatment of fibromyalgia (Arnold, Goldenberg, Stanford, et al., 2007). Patients received either gabapentin (1200 to 2400 mg/day) or placebo for 12 weeks. Those who took gabapentin experienced significant improvements in quality of life and functional outcomes and a 51% reduction in pain compared with 31% in the placebo group.


Central neuropathic pain such as from stroke or spinal cord injury can be particularly difficult to treat. An 18-week trial randomized 20 patients with traumatic spinal cord injury to receive gabapentin or placebo during a 4-week titration period followed by a 4-week stable dosing period. After a 2-week washout period, patients were crossed over to the alternative treatment for 4 weeks of titration followed by a 4-week stable dosing period (Levendoglu, Ogun, Ozerbil, et al., 2004). During the period of treatment with the active drug, an effort was made to titrate the dose to 900 mg/day by the end of the first week, 1800 mg/day by the second week, 2400 mg/day by the third, and 3600 mg/day by the fourth. Patients received the maximum tolerated dose during the 4 weeks of stable dosing. All patients completed the study, and gabapentin was shown to be efficacious for neuropathic pain, including all types of neuropathic phenomena except sensations described as itchy, sensitive, dull, and cold. Quality of life was also improved.


A retrospective study of 38 patients with central pain found similar dramatic results during gabapentin treatment, with improvements in sharp, burning pain and numerous quality of life and functional indicators such as ability to sleep and participate in domestic activities (To, Lim, Hill, et al., 2002). Some patients in this study reported that life would be unbearable without gabapentin. The range of dosing was 900 to 4800 mg/day. Follow-up interviews with 21 patients with traumatic spinal cord injury who were treated with gabapentin found that 67% reported a favorable response at 6-month interview, and 91% of these continued to report effective pain relief at 36-month interview (Putzke, Richards, Kezar, et al., 2002).


Gabapentin is also effective as an adjuvant to opioid analgesia for neuropathic pain treatment. A randomized controlled trial of 57 patients with postherpetic neuralgia or diabetic neuropathy administered placebo, gabapentin alone, morphine alone, or gabapentin plus morphine (Gilron, Bailey, Tu, et al., 2005). Pain relief was best with the combination of morphine plus gabapentin, and the maximum tolerated doses of gabapentin and morphine were lower with the combination than for each drug alone. Similar results have been found when gabapentin is added to opioids for neuropathic cancer pain, particularly if the patient has allodynia and burning, shooting pain (Caraceni, Zecca, Martini, et al., 1999; Keskinbora, Pekel, Aydinli, 2007). Its effectiveness for these symptoms was supported in a systematic review of randomized controlled trials that concluded that the drug was particularly effective in relieving the neuropathic symptoms of allodynia, burning pain, shooting pain, and hyperesthesia (Backonja, Glanzman, 2003).


Not all studies in neuropathic pain have yielded positive results. In an 8-week 3-phase crossover trial (N = 38) that compared gabapentin, amitriptyline, and diphenhydramine (Benadryl) for spinal cord injury–related pain, gabapentin was no more effective than diphenhydramine in patients who had the highest baseline pain scores; amitriptyline was more effective than diphenhydramine (Rintala, Holmes, Courtade, et al., 2007) (see Chapter 31 for more on antihistamines).


Although gabapentin frequently is given to patients with chemotherapy-induced peripheral neuropathy (Mao, Chen, 2000a), few controlled trials have been conducted, and investigations have shown conflicting results. A phase III multicenter, placebo-controlled, randomized trial (N = 115) using gabapentin for this type of pain failed to show any significant benefits (Rao, Michalak, Sloan, et al., 2007). However, another study grouped 75 patients with chemotherapy-induced neuropathy into three categories according to the severity of their pain (mild, moderate, or severe) and administered all of them a fixed dose of 800 mg/day of gabapentin (Tsavaris, Kopterides, Kosmas, et al., 2008). Results in these groups were compared with a control group that received naproxen and codeine plus acetaminophen. Of those who received gabapentin, approximately 25% had complete relief, 44% had partial relief, 25% had minor relief, and 5% had no relief. Of those in the control group, none had complete relief, approximately 5% had partial relief, 46% had minor relief, and 49% had no relief.


Small trials in phantom pain produced generally favorable results. A 14-week, randomized controlled trial that included 19 patients with phantom limb pain noted that gabapentin (titrated to 2400 mg) reduced pain but had no significant effect on mood, sleep interference, or activities of daily living compared with placebo (Bone, Critchley, Buggy, 2002). A report on 7 children and young adults with phantom limb pain revealed that 6 of the 7 had resolution of their phantom limb pain within 2 months of gabapentin treatment (Rusy, Troshynski, Weisman, 2001).


Some types of back pain may be responsive to anticonvulsants such as gabapentin (Backonja, Glanzman, 2003). One guideline suggests that gabapentin may provide short-term benefit for painful radiculopathy, but also concludes that evidence is limited and all but lacking for other anticonvulsants (Chou, Qaseem, Snow, et al., 2007).


The foregoing describes a small proportion of the large number of clinical trials, case reports, and reviews that have addressed the analgesic potential of gabapentin. A broader review of this literature reveals publications on the following conditions:



• Postherpetic neuralgia (Backonja, Glanzman, 2003; Chou, Carson, Chan, 2009; Dubinsky, Kabbani, El-Chami, et al., 2004; Mao, Chen, 2000a; Rosenberg, Harrell, Ristic, et al., 1997; Rice, Maton, Postherpetic Neuralgia Study Group, 2001; Rosner, Rubin, Kestenbaum, 1996; Rowbotham, Harden, Stacey, et al., 1998; Serpell, Neuropathic Pain Study Group, 2002)


• Painful diabetic neuropathy (Argoff, Backonja, Belgrade, et al., 2006; Backonja, Beydoun, Edwards, et al., 1998; Backonja, Glanzman, 2003; Boulton, Vinik, Arezzo, et al., 2005; Chou, Carson, Chan, 2009; Dallocchio, Buffa, Mazzarello, et al., 2000; Duby, Campbell, Setter, et al., 2004; Gilron, Bailey, Tu, et al., 2005; Hemstreet, Lapointe, 2001; Jensen, Larson, 2001; Mao, Chen, 2000a; Serpell, Neuropathic Pain Study Group, 2002; Veves, Backonja, Malik, 2008)


• Fibromyalgia (Arnold, Goldenberg, Stanford, et al., 2007) (see also Hauser, Thieme, Turk, 2009)


• Neuropathic cancer pain (Caraceni, Zecca, Martini, et al., 1999; Keskinbora, Pekel, Aydinli, 2007)


• Chemotherapy-induced pain (Mao, Chen, 2000a; Tsavaris, Kopterides, Kosmas, et al., 2008)


• Central pain from spinal cord injury (To, Lim, Hill, et al., 2002; (Levendoglu, Ogun, Ozerbil, et al., 2004)


• Central poststroke pain (Frese, Husstedt, Ringelstein, et al., 2006; Kumar, Kalita, Kumar, et al., 2009; Serpell, Neuropathic Pain Study Group, 2002)


• Multiple sclerosis (Mao, Chen, 2000a)


• Phantom limb pain (Bone, Critchley, Buggy, 2002; Serpell, Neuropathic Pain Study Group, 2002)


• CRPS (Backonja, Glanzman, 2003; Mao, Chen, 2000a; Mellick, Mellick, 1995; Serpell, Neuropathic Pain Study Group, 2002)


• Radiculopathy (Serpell, Neuropathic Pain Study Group, 2002)


• HIV-related neuropathy (Rosner, Rubin, Kestenbaum, 1996; Hahn, Arendt, Braun, et al., 2004)


• Spinal stenosis (Yaksi, Ozgonenel, Ozgonenel, 2007)


• Atypical facial pain and trigeminal neuralgia (Mao, Chen, 2000a; Serpell, Neuropathic Pain Study Group, 2002)


• Cluster and migraine headache (Kaniecki, 2008; Mathew, 2001; Tay, Ngan Kee, Chung, 2001)


• Neuroma of peripheral nerve (Serpell, Neuropathic Pain Study Group, 2002)


• Persistent neuropathic postsurgical pain syndromes (e.g., postmastectomy, postthoractomy, post inguinal hernia, cholecystectomy) (Backonja, Glanzman, 2003; Mao, Chen, 2000a; Pandey, Patra, Pant, et al., 2006; Serpell, Neuropathic Pain Study Group, 2002; Tiippana, Hamunen, Kontinen, et al., 2007)


• Persistent back pain (Backonja, Glanzman, 2003; Chou, Qaeem, Snow, et al., 2007; Serpell, Neuropathic Pain Study Group, 2002)


• Persistent masticatory muscle pain (Kimos, Biggs, Mah, et al., 2007)


• Guillain-Barré syndrome (Mao, Chen, 2000a; Pandey, Bose, Garg, et al., 2002)


• Vulvodynia (Ben-David, Friedman, 1999)



Pregabalin


Pregabalin (Lyrica) is a newer gabapentinoid and a precursor to gabapentin. It has a similar mechanism of action and many of the same pharmacologic properties, but has different pharmacokinetics and can exert a different profile of effects than gabapentin in the individual patient.


The oral bioavailability of gabapentin is 27% to 60%, depending on dose (Lacy, Armstrong, Goldman, et al., 2008), and 90% for pregabalin (Gajraj, 2007). Similar to gabapentin, pregabalin is not metabolized and is essentially unchanged with renal elimination. Neither drug has known drug-drug interactions.


The onset of pregabalin analgesia is approximately 25 minutes (Hill, Balkenohl, Thomas, et al., 2001), compared with 1 to 3 hours for gabapentin (Twycross, Wilcock, Charlesworth, et al., 2003). This faster onset of analgesic action may be clinically relevant in some cases (Blommel, Blommel, 2007). Equally important, pregabalin can be more rapidly titrated to the typical effective dose range than gabapentin. The time to effective dose for pregabalin may be as brief as 1 to 2 days (Gajraj, 2007; Portenoy, Murphy, Young, et al., 2006), compared to approximately 9 days for gabapentin (Gajraj, 2007). (See Chapter 26 for the perioperative use of pregabalin.)


Gabapentin is not a controlled substance, but pregabalin is designated a Schedule V drug. The Drug Enforcement Administration (DEA) reportedly designated pregabalin as a Schedule V drug because it produces some pharmacologic effects similar to diazepam (Valium) and alprazolam (Xanax); however, the data to support this conclusion are limited, and the effects are not sustained over time (Blommel, Blommel, 2007).


Pregabalin is approved in the United States for treatment of postherpetic neuralgia, painful diabetic neuropathy, and fibromyalgia. In the latter condition, studies have shown that the drug improves several core symptoms including pain, fatigue, and overall health and function (Arnold, Russell, Diri, et al., 2008; Crofford, Rowbotham, Mease, et al., 2005; Lyseng-Williamson, Siddiqui, 2008).


Although pregabalin may have effects on co-morbid anxiety, as suggested in a positive trial in patients with central pain from spinal cord injury (Murphy, Siddall, Griesing, 2007), a controlled trial in fibromyalgia patients demonstrated that anxiolysis was not necessary for pain reduction (Arnold, Crofford, Martin, et al., 2007). Studies show that pregabalin also can reduce pain-related sleep interference (Freynhagen, Grond, Schupfer, et al., 2007; Lesser, Sharma, LaMoreaux, et al., 2004; Sabatowski, Galvez, Cherry, et al., 2004; van Seventer, Feister, Young, 2006). Compared with alprazolam (Xanax) and placebo in healthy volunteers without pain, pregabalin produced improvements in features of disturbed sleep that have been reported in patients with fibromyalgia and anxiety disorders (Hindmarch, Dawson, Stanley, 2005).


Recent evidence-based guidelines indicate that pregabalin (or gabapentin) should be considered the first-line drug for the treatment of postherpetic neuralgia, painful diabetic neuropathy, and other neuropathic pains, unless a co-morbid depression suggests that an analgesic antidepressant should be tried first (Argoff, Backonja, Belgrade, et al., 2006; Dworkin, O’Connor, Backonja, et al., 2007) (see Chapter 22). This conclusion gains support from the consistent results observed in randomized controlled trials.


A 4-week randomized, placebo-controlled trial (N = 269) showed that pregabalin produced significant reductions in the spontaneous pain and allodynia caused by postherpetic neuralgia (Stacey, Barrett, Whalen, et al., 2008). An interesting finding was that improvements in pain and allodynia were correlated, which led the researchers to suggest allodynia could serve as an outcome measure in future research of this type. This trial compared fixed (300 mg/day) and flexible (150 to 600 mg/day) dosing regimens, and the latter was recommended as a way to reduce discontinuations, facilitate higher final doses, and improve ultimate pain relief. Flexible dosing of pregabalin has been recommended by others as well (Baron, Brunnmuller, Brasser, et al., 2007; Freynhagen, Grond, Schupfer, et al., 2007; Freynhagen, Strojek, Griesing, et al., 2005; Rowbotham, Stacey, Phillips, et al., 2007; Vranken, Dijkgraaf, Kruis, et al., 2008) (see later discussion of dosing recommendations).


In a recent meta-analysis of placebo-controlled trials in populations with painful diabetic neuropathy, pregabalin treatment yielded pain reduction; higher quality of life scores; and increased risk of dizziness, sedation, and edema (Hurley, Lesley, Adams, et al., 2008). Others have found similar results (Richter, Portenoy, Sharma, et al., 2005; Rosenstock, Tuchman, LaMoreaux, et al., 2004). A systematic review of research conducted between 1966 and 2005 concluded that pregabalin had a lower number-needed-to-treat (NNT = 3.24) for achieving greater than 50% analgesia in patients with painful diabetic neuropathy than any other anticonvulsants studied (Gutierrez-Alvarez, Beltran-Rodriguez, Moreno, 2007).


Positive findings also have been demonstrated in the treatment of central pain caused by spinal cord injury or stroke. A 4-week randomized, placebo-controlled trial of a flexible dosing regimen of pregabalin in 40 patients with central pain from brain or spinal cord injury demonstrated significant decreases in mean pain score and improvements in health status, but no difference in Pain Disability Index scores on follow-up evaluation compared with placebo (Vranken, Dijkgraaf, Kruis, et al., 2008).


The safety and effectiveness of pregabalin was evaluated in several open-label trials. A study of 55 patients with diverse types of refractory pain in which each patient’s physician prescribed pregabalin with or without other analgesics according to their own preferences observed a reduction in the mean pain score from 6.5 at baseline to 5.5 on day 14 and to 4.9 on day 28; associated improvements in quality of life, sleep, and functional outcomes; and no serious adverse effects (Freynhagen, Grond, Schupfer, et al., 2007). A review of the open-label extension phases following 7 placebo-controlled trials reported that pain levels remained constant without clinically meaningful dose variations over a 2-year follow-up period (Portenoy, Murphy, Young, et al., 2006). A 15-month open-label trial that incorporated flexible dosing of pregabalin demonstrated persistent positive drug effects in a subset of patients (N = 81) with postherpetic neuralgia or painful diabetic neuropathy refractory to other adjuvant analgesics (e.g., gabapentin and antidepressants) (Stacey, Dworkin, Murphy, et al., 2008). Almost half of the patients had a greater than 30% reduction in pain, and the prevalence of severe pain declined from 63% on admission to the trial to only 23% after 15 months of pregabalin treatment; when pregabalin was stopped during the study drug holidays, pain rapidly returned. Because patients were allowed to continue to take their other analgesics during this study, pregabalin was seen as an add-on therapy, and the researchers cautioned that the results should be interpreted with this in mind.


The prior studies are representative of a larger literature documenting the clinical trials, case reports, and reviews that have evaluated the analgesic potential of pregabalin. Recent studies also suggest that the drug may have utility in several nonpainful conditions (Ehrchen, Stander, 2008; Porzio, Aielli, Verna, et al., 2006) and restless leg syndrome pain (Sommer, Bachmann, Liebetanz, et al., 2007). A broad review of the literature on pregabalin reveals publications on the following conditions:



• Painful diabetic neuropathy (Argoff, Backonja, Belgrade, et al., 2006; Baron, Brunnmuller, Brasser, et al., 2007; Boulton, Vinik, Arezzo, et al., 2005; Frampton, Scott, 2004; Frank, Cousins, 2008; Freeman, Durso-Decruz, Emir, 2008; Freynhagen, Strojek, Griesing, et al., 2005; Freynhagen, Grond, Schupfer, et al., 2007; Richter, Portenoy, Sharma, et al., 2005; Rosenstock, Tuchman, LaMoreaux, et al., 2004; Tolle, Freynhagen, Versavel et al., 2008; Veves, Backonja, Malik, 2008)


• Fibromyalgia (Arnold, Crofford, Martin, et al., 2007; Arnold, Russell, Diri, et al., 2008; Crofford, Rowbotham, Mease, et al., 2005) (see also Hauser, Thieme, Turk, 2009.)


• Postherpetic neuralgia (Baron, Brunnmuller, Brasser, et al., 2007; Dubinsky, Kabbani, El-Chami, et al., 2004; Dworkin, Corbin, Young, et al., 2003; Frampton, Foster, 2005; Freynhagen, Strojek, Griesing, et al., 2005; Rowbotham, Stacey, Phillips, et al., 2007; Stacey, Barrett, Whalen, et al., 2008; van Seventer, Feister, Young, et al., 2006)


• Central pain from brain or spinal cord injury (Siddall, Cousins, Otte, et al., 2006; Vranken, Dijkgraaf, Kruis, et al., 2008)


• Trigeminal neuralgia (Obermann, Yoon, Sensen, et al., 2008)


• Glossopharyngeal neuralgia (Guido, Specchio, 2006)


• Restless leg syndrome with or without neuropathic pain (Sommer, Bachmann, Liebetanz, et al., 2007).



Lamotrigine


A recent meta-analysis of clinical trials evaluating lamotrigine (Lamictal) for acute and persistent pain showed limited efficacy for neuropathic pain states and no studies on its use for acute pain (Wiffen, Rees, 2007). In practice, the drug may be tried in those with persistent neuropathic pain that has not responded to the gabapentinoids and one or more of the analgesic antidepressants. The limited data supporting the potential for analgesic efficacy includes randomized trials for trigeminal neuralgia (Zakrzewska, Chaudhry, Nurmikko, et al., 1997), HIV painful neuropathy (Simpson, Olney, McArthur, et al., 2000), and central poststroke pain (Frese, Husstedt, Ringelstein, et al., 2006; Kumar, Kalita, Kumar, et al., 2009; Vestergaard, Andersen, Gottrup, et al., 2001). Open-label trials suggest analgesic effects in trigeminal neuralgia (Canavero, Bonicalzi, 1997; Rosen, 2001), sciatic pain (Eisenberg, Damunni, Hoffer, et al., 2003), and pain associated with multiple sclerosis (Cianchetti, Zuddas, Randazzo, et al., 1999). In contrast, studies in populations with painful diabetic neuropathy have yielded conflicting results (Duby, Campbell, Setter, et al., 2004; Eisenberg, Alon, Ishay, et al., 1998; Jose, Bhansali, Hota, et al., 2007; Vinik, Tuchman, Safirstein, et al., 2007), and a controlled study that evaluated the addition of lamotrigine (up to 400 mg/day) to either a nonopioid analgesic, gabapentin, or a tricyclic antidepressant (TCA) for a variety of different types of neuropathic pains did not reveal an analgesic response (Silver, Blum, Grainger, et al., 2007).


Lamotrigine carries a relatively high risk of rash—up to 7% of patients in some studies—and serious cutaneous hypersensitivity (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). This adverse effect occurs far more frequently with lamotrigine than during treatment with other adjuvant analgesics. The latter risk is increased in younger patients, and the drug should not be used in patients younger than 15 years old. Although the risk of serious rash in adults is low overall (less than 1%), the availability of other agents (e.g., antidepressants and other anticonvulsants) with less of this risk suggests that lamotrigine may best be relegated to a trial only after several other drugs have failed to provide benefit. If a lamotrigine trial is undertaken, dosing should follow the manufacturer’s recommendation for gradual titration from a low dose, which has been determined to reduce the risk of cutaneous toxicity.



Oxcarbazepine


Another relatively new anticonvulsant is oxcarbazepine (Trileptal), which structurally is a metabolite of carbamazepine (Tegretol). It is approved in the United States for the treatment of trigeminal neuralgia and has been described as the drug of choice for this condition (Carrazana, Mikoshiba, 2003; Jensen, 2002). Simple dose titration and dose adjustments and convenient twice-daily dosing are cited among the advantages of this drug. A meta-analysis supports effectiveness comparable to carbamazepine but with fewer adverse effects; 62% reported good to excellent tolerability with oxcarbazepine compared with 48% who took carbamazepine (Beydoun, Schmidt, D’Souza, et al., 2002). Open-label studies support these findings as well (Carrazana, Mikoshiba, 2003).


In contrast to the studies in trigeminal neuralgia, studies in diabetic painful neuropathy have yielded equivocal results. A 16-week randomized, placebo-controlled study (N = 146) titrated patients with painful diabetic neuropathy to a maximum dose of 1800 mg/day and reported a larger decrease in average visual analog scale (VAS) score (–24.3) compared with placebo (–14.7) (Dogra, Beydoun, Mazzola, et al., 2005). More patients had a greater than 50% reduction in pain with oxcarbazepine (35.2%) than with placebo (18.4%), and there were fewer arousals from sleep because of pain in those who took the active drug. Another large placebo-controlled trial (N = 347) evaluating the drug for painful diabetic neuropathy found a trend toward meaningful changes in pain scores from baseline to the last week of the study with oxcarbazepine 1200 mg/day and 1800 mg/day compared with placebo, but the changes did not reach statistical significance (Beydoun, Shaibani, Hopwood, et al., 2006). A 9-week open-label trial in 30 patients with painful diabetic neuropathy found that oxcarbazepine (highest dose of 1200 mg/day) produced significant improvements in pain relief, with a decrease in mean VAS score from 66.3 at baseline to 34.3 at the end of the trial (Beydoun, Kobetz, Carrazana, 2004). The most common adverse effects were sedation and dizziness, similar to other anticonvulsants.


The efficacy of oxcarbazepine has been studied in other conditions as well. A randomized controlled trial of 32 patients with colon cancer undergoing chemotherapy found a dramatically lower incidence of chemotherapy-induced neuropathy when oxcarbazepine was administered prior to chemotherapy (31.2%) compared with chemotherapy without oxcarbazepine (75%) (Argyriou, Chroni, Polychronopoulos, 2006). In contrast, a controlled study of patients with frequent migraine was negative, demonstrating no reduction in the number of attacks over 28 days of prophylactic treatment (Silberstein, Saper, Berenson, et al., 2008). Efficacy in postherpetic neuralgia and CRPS has been suggested in published case reports (Criscuolo, Auletta, Lippi, et al., 2004; Lalwani, Shoham, Koh, et al., 2005). Further research and clinical experience with this drug are needed to better evaluate its safety and what types of pain will benefit most (Guay, 2003).



Topiramate


Topiramate (Topamax) is approved in the United States for migraine prevention. A multicenter, double-blind study randomized 487 people with persistent migraine to receive placebo, or 50, 100, or 200 mg of topiramate daily for 26 weeks to determine efficacy and optimal dose (Silberstein, Neto, Schmitt et al., 2004). The percent of individuals who experienced 50% or greater reduction in monthly migraine were: 23% (placebo), 36% (50 mg), 54% (100 mg), and 52% (200 mg) (see dosing guidelines later in this chapter). Topiramate treatment also resulted in a reduction in the use of acute headache treatment medications in this study. The most frequent adverse effects were paresthesia, fatigue, nausea, anorexia, and abnormal taste. Weight loss, a common effect of topiramate, was experienced in those taking 100 and 200 mg. Other randomized controlled trials similarly support 100 mg/day as the most efficacious and best-tolerated dose of topiramate for migraine prevention (Brandes, Saper, Diamond, et al., 2004; Silberstein, 2005; Silberstein, Diener, Lipton, et al., 2008; Silberstein, Lipton, Dodick, et al., 2007).


Topiramate also has been shown to be effective for persistent cluster headache (Lainez, Pascual, Pascual, et al., 2003), idiopathic trigeminal neuralgia (Solaro, Uccelli, Brichetto, et al., 2001), and trigeminal autonomic cephalalgias, which is a grouping of headache syndromes that include paroxysmal hemicrania and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome in addition to cluster headache (Cohen, Matharu, Goadsby, 2007; May, Leone, Afra, et al., 2006).


Topiramate has been studied for other types of persistent pain, with equivocal outcomes. A 10-week randomized placebo-controlled trial (N = 96) demonstrated that topiramate titrated to a maximum dose of 300 mg/day was safe and significantly improved pain, quality of life, and functional outcomes in a group of patients with persistent low back pain (Muehlbacher, Nickel, Kettler, et al., 2006). Again, weight loss was notable in this study, which may be a significant benefit in some patients with persistent pain who are also overweight. A small pilot study of 4 patients with phantom limb pain showed that 3 of the 4 experienced significant decreases in pain with topiramate (Harden, Houle, Remble, et al., 2005); the peak effect was noted at 800 mg/day, but such high doses are not recommended (United States Food and Drug Administration [U.S. FDA], 2004). Topiramate has not been shown to be effective for painful diabetic neuropathy (Jensen, 2002), and guidelines list it as a drug with limited evidence for treatment of this condition (Argoff, Backonja, Belgrade, et al., 2006).


Metabolic acidosis caused by renal wasting of bicarbonate has been linked to the use of topiramate. Mild to moderate decreases in serum bicarbonate are most likely at doses of 400 mg/day and usually occur early in treatment; however, these effects have also been noted in doses as low as 50 mg/day (U.S. FDA, 2004). These effects are of particular concern when the drug is used on a long-term basis (Welch, Graybeal, Moe, et al., 2006). Nephrolithiasis also has been noted.



Other Second-Generation Anticonvulsants


Very few studies have evaluated the analgesic potential of zonisamide (Zonegran). A study that randomized 25 patients with painful diabetic neuropathy to receive placebo or zonisamide found that a mean dose of 540 mg/day over 6 weeks was associated with a nonsignificant improvement in pain (Atli, Dogra, 2005). A larger sample size would have likely demonstrated analgesic efficacy in this trial, but the dropout rate was high due to a variety of adverse effects (e.g., irritability, insomnia, metallic taste, and rash) in those taking zonisamide. Given the limited data, this drug is rarely tried for patients with neuropathic pain or migraine (Kaniecki, 2008), and further research is needed to evaluate its efficacy and safety for these conditions (Duby, Campbell, Setter, et al., 2004; Guay, 2003).


Lacosamide (Vimpat) was recently approved in the United States for the indication of seizures. There are data suggesting analgesic efficacy in painful diabetic neuropathy. A randomized controlled trial (N = 119) found lacosamide titrated to 100 to 400 mg/day or maximum tolerated dose produced significantly better pain relief and improvements in quality of life compared with placebo in patients with moderate to severe intensity painful diabetic neuropathy (Rauck, Shaibani, Bilton, et al., 2007). An open-label trial (N = 69) demonstrated both short-term and long-term (2.5 years) safety and efficacy at maximum titrated doses of 400 mg/day in patients with painful diabetic neuropathy (Shaibani, Biton, Rauck, et al., 2009). Other studies have produced similar findings (Hidvegi, Bretschneider, Thierfelder, et al., 2008; Kenney, Simpson, Koch, et al., 2006; Shaibani, Fares, Selam, et al., 2009). Long-term safety and efficacy was established for 400 mg/day of lacosamide for 18 weeks in a double-blind, randomized, placebo-controlled trial of 370 patients with painful diabetic neuropathy (Wymer, Simpson, Sen, et al., 2009). The lower dose of 200 mg/day reduced pain but failed to significantly dissociate from placebo for primary and secondary outcome measures.


No substantial metabolism, low or no inhibition of cytochrome P450 isoenzymes, and low protein binding contribute to a low incidence of drug-drug interactions with lacosamide (Kropeit, Scharfenecker, Schiltmeyer, et al., 2006). There is no interaction between lacosamide and the oral antidiabetic drug metformin, which is an advantage in patients who take that drug for diabetes and also have painful diabetic neuropathy (Schiltmeyer, Kropeit, Cawello, et al., 2006).


Tiagabine (Gabitril) is used for treatment of a wide variety of conditions including epilepsy and other seizure disorders, depression, anxiety, posttraumatic stress syndrome, and substance withdrawal symptoms. There has been little investigation of its analgesic potential. A 3-month, open-label study comparing tiagabine and gabapentin in 91 patients with persistent pain, such as back pain, musculoskeletal headache, and fibromyalgia, found that both drugs significantly reduced pain, but tiagabine showed greater improvements in sleep quality (Todorov, Kolchev, Todorov, 2005). The drug has been linked to new-onset seizures, which have occurred at doses as low as 4 mg/day and usually occur after dose increases; this adverse effect led the United States Food and Drug Administration (2005b) to recommend discontinuation of the drug in nonepileptic patients who develop seizures.


Felbamate (Felbatol) has been used anecdotally to treat hemifacial spasm (Mellick, 1995), a painless syndrome characterized by paroxysmal contraction of facial muscles. Although this observation and treatment of a small number of patients initially raised expectations, no follow-up studies have been done in populations with pain. The potential for lethal aplastic anemia from this drug has tempered enthusiasm for these trials (see adverse effects).



First-Generation Anticonvulsants


The older anticonvulsants have been used as analgesics for several decades. Although the newer drugs are now preferred, patients with refractory pain may be offered trials of these drugs.



Carbamazepine


Carbamazepine (Tegretol) has been reported to be effective for many pain syndromes, including diabetic neuropathy, postherpetic neuralgia, poststroke pain, and CRPS (Dobecki, Schocket, Wallace, 2006; Harke, Gretenkort, Ladleif, et al., 2001; Vurdelja, Budincevic, Prvan, 2008; Zin, Nissen, Smith, et al., 2008). It is approved for treatment of trigeminal neuralgia, and based on years of positive experience in this syndrome, often is selected as a first-line drug (Jensen, 2002; Jensen, Finnerup, 2007; Krafft, 2008; Sindrup, Jensen, 2002) (see also oxcarbazepine). Carbamazepine also has been used to treat cancer-related pruritus (Korfitis, Trafalis, 2008). A systematic review of controlled trials concluded that carbamazepine has analgesic properties for varied acute and persistent pains and can treat lancinating neuropathic pain, regardless of the specific pathologic condition contributing to the presence of this pain characteristic (Wiffen, McQuay, Moore, 2005). Although the numbers of patients in these clinical trials were small, clinicians wanting to use this agent as a second-line anticonvulsant can access important information as to how effective it is with certain types of pain from this review.



Clonazepam


Clonazepam (Klonopin) is a benzodiazepine and has been used primarily as an anticonvulsant. It has been suggested to be analgesic in the lancinating pain associated with phantom limb pain, neuropathic cancer-related pain, and myofascial pain (Bartusch, Sanders, D’Alessio, et al., 1996; Hugel, Ellershaw, Dickman, 2003; Fishbain, Cutler, Rosomoff, et al., 2000). The supporting evidence is very limited, however, and its use may be more related to its potential to help co-morbid anxiety than to its established analgesic efficacy. Given its long half-life, the potential for accumulation with repeated dosing must be recognized, and it must be used very cautiously in patients predisposed to adverse effects, including the cognitively impaired (particularly older adults) and patients with sleep apnea syndrome or advanced cardiopulmonary disease. (See clonazepam patient medication information, Form V-3 on pp. 763-764, at the end of Section V.)



Divalproex Sodium and Valproic Acid


Divalproex sodium (Depakote) is approved and widely used for migraine prevention (Freitag, Diamond, Diamond, et al., 2001; Silberstein, Collins, 1999). The drug is closely related to valproic acid and shares the same pharmacology, but differs in that it is available in gastro-resistant sprinkles and modified-release formulation. In a 12-month, open-label study of 241 adolescents with migraines who were given a titrated dose of modified-release divalproex to a maximum dose of 1000 mg/day, the median number of migraine attacks decreased 75% between the first and fourth month of the study and remained at or below this level for the remainder of the study (Apostol, Lewis, Laforet et al., 2009). The most common adverse effects were nausea, vomiting, and weight gain; 17% discontinued therapy because of an adverse event.


Divalproex sodium has not been studied in neuropathic pain, and the evidence for valproic acid is mixed. Whereas one study showed improvements in painful diabetic neuropathy (Kochar, Rawat, Agrawal, et al., 2004), another found no benefit in pain from polyneuropathy (Otto, Bach, Jensen, et al., 2004). Based on the limited data (Chong, Hester, 2007), divalproex sodium is rarely tried for neuropathic pain, and the IV formulation of valproic acid (Depacon) is only occasionally used in an effort to quickly reverse severe pain, typically in an inpatient setting.



Phenytoin


Similar to carbamazepine, phenytoin (Dilantin) has been used as an analgesic for decades, but has been largely supplanted by newer anticonvulsants (Jensen, 2002; Vanotti, Osio, Mailland, et al., 2007). In early controlled trials, phenytoin was shown to be an effective analgesic for neuropathic pain, particularly pains characterized by a prominent lancinating component (McCleane, 1999). Isolated case reports illustrate its use, and one in particular that shows it has benefits for treating crescendo pelvic cancer–related pain with lancinating quality (Chang, 1997). IV phenytoin, like IV valproate, is sometimes suggested as an option for treatment of acute attacks of neuropathic pain (Jensen, 2002; McCleane, 1999). An extensive review (Duby, Campbell, Setter, et al., 2004) and guidelines (Argoff, Backonja, Belgrade, et al., 2006) list phenytoin as a drug with limited evidence for treatment of painful diabetic neuropathy.




Mechanism of Action


The specific mechanisms of the analgesia produced by anticonvulsant drugs are not known, but presumably relate to those actions underlying anticonvulsant effects (Lussier, Portenoy, 2004). Most of the anticonvulsants have multiple mechanisms of action (Gilron, 2006), and these may differ among the various anticonvulsants (Lussier, Portenoy, 2004).


One of the mechanisms is blockade of presynaptic voltage-gated ion channels, which prevents the generation of spontaneous ectopic discharges (Beydoun, Backonja, 2003; Taylor, 2009) (see Section I and Figure I-2, B on pp. 4-5). Some anticonvulsants (e.g., carbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, topiramate, and zonisamide) relieve pain, in part, by prolonging the recovery phase of sodium channels after their activation (Gilron, 2006; Soderpalm, 2002). Some (e.g., carbamazepine, felbamate, gabapentin, lamotrigine, pregabalin, valproic acid, and zonisamide) bind to presynaptic voltage-gated calcium channels and inhibit calcium influx and the release of excitatory neurotransmitters from primary afferent nerve fibers (Dickenson, Matthews, Suzuki, 2002; Gajraj, 2007; Gilron, 2006; Taylor, 2009; Tiippana, Hamunen, Kontinen, et al., 2007). Pregabalin has an even higher calcium-channel affinity than gabapentin and has no effect on sodium channels (Gilron, Watson, Cahill, et al., 2006; Mao, Chen, 2000a; Nicholson, 2000). Recent research confirmed that gabapentin had no effect on transient sodium currents but inhibited persistent sodium currents in a dose-dependent way (Yang, Wang, Chen, et al., 2009). The clinical significance of these findings is unknown.


Other mechanisms also may be important. Inhibition of glutamate, an excitatory neurotransmitter that promotes the transmission of pain through increased activity at the NMDA receptor and other receptors, may be relevant for some drugs (Jensen, 2002; Soderpalm, 2002) (see Section I and Figure I-2, B on pp. 4-5). Others may indirectly or directly augment inhibitory GABAergic neurotransmission (Gilron, 2006; Soderpalm, 2002). For example, gabapentin is a GABA analogue, and although it does not bind to GABA receptors or modulate GABA reuptake, it does enhance overall GABA-mediated inhibitory tone (Dickenson, Matthews, Suzuki, 2002; Jensen, 2002; Mao, Chen, 2000). Gabapentin and pregabalin share a specific high affinity drug binding site (calcium channel α2-δ ligands) localized at synapses and sufficient in amount to account for their analgesic action (Taylor, 2009).


Interestingly, there is evidence that some of the anticonvulsants have peripheral effects that may be involved in pain. For example, carbamazepine and phenytoin produce antiinflammatory effects, and local injection of gabapentin and lamotrigine in animals exerts an analgesic effect (Gilron, 2006).


The central effects of anticonvulsants have been evaluated in experimental studies. Animal and human research has shown that gabapentin selectively reduces nociception in a sensitized (damaged) nervous system but not in a normal nervous system (Gilron, 2002). Healthy volunteers in two separate randomized, placebo-controlled studies were subjected to experimental thermal injury (acute pain model [nociception]) (Werner, Perkins, Holte, et al., 2001) and heat-capsaicin sensitization (central hypersensitivity model [neuropathic]) (Dirks, Petersen, Rowbotham, et al., 2002). Gabapentin was found to have no effect on pain transmission on normal skin but significantly reduced hyperalgesia. Gilron (2002) pointed out that the clinical value of these findings is that gabapentin may reduce pathologic (neuropathic) pain while leaving other protective nociceptive mechanisms intact.



Adverse Effects


Anticonvulsants usually are well-tolerated (Collins, Moore, McQuay, et al., 2000). The most common adverse effects are dizziness and sedation. These are usually transient and most notable during the titration phase of treatment (Serpell, Neuropathic Pain Study Group, 2002). GI upset (e.g., nausea) can occur but usually decreases with time. Occasionally, patients report changes in mood, such as dysphoria or cognitive impairment, which may be subtle.


There is a long history of concern about the association between anticonvulsant use and loss of bone mineral density (Sheth, 2005), particularly during treatment with enzyme-inducing anticonvulsants, such as carbamazepine and phenytoin (Petty, Paton, O’Brien, et al., 2005). Risk factors for this adverse effect are ages 40 years and older and anticonvulsant use for more than 2 years. Gabapentin, pregabalin, lamotrigine, and topiramate are examples of non–enzyme-inducing anticonvulsants (Novy, Stupp, Rossetti, 2009). Valproate is a non–enzyme-inducing anticonvulsant but it is associated with reduced bone mineralization (Novy, Stupp, Rossetti, 2009).


Although there have been case reports of hepatotoxicity with gabapentin (Richardson, Williams, Kingham, 2002), they are rare. Neither gabapentin nor pregabalin undergo hepatic metabolism, a positive effect of which is a minimal risk of drug-drug interactions (Frank, Cousins, 2008). The new anticonvulsant, lacosamide, produces low or no inhibition of cytochrome P450 isoenzymes and also may have a reduced risk of interactions (Kropeit, Scharfenecker, Schiltmeyer, et al., 2006). Other anticonvulsants inhibit various isoenzymes of the cytochrome P450 enzyme system, which can result in drug-drug interactions (Virani, Mailis, Shapiro, et al., 1997) (see Chapter 11, for more on the cytochrome P450 enzyme system). Each anticonvulsant has a unique profile (LaRoche, 2007), and it is important for the clinician to become familiar with the potential for drug-drug interactions associated with the particular anticonvulsant being administered. Patients must be told to report adverse effects promptly, and in some cases serum drug concentrations should be closely monitored to prevent toxicity, such as in patients who take multiple other medications and those who take anticonvulsants during chemotherapy (Yap, Chui, Chan, 2008). Following is a more detailed discussion of adverse effects associated with selected anticonvulsants.



Gabapentin


Gabapentin has a relatively low adverse effect profile, and in clinical practice dizziness and sedation seem to be the most dose-limiting adverse effects. A meta-analysis of 36 randomized, placebo-controlled studies of several of the second-generation anticonvulsants used for seizure control confirmed that gabapentin was significantly associated with sedation and dizziness; however, comparisons between drugs were not possible (Zaccara, Gangemi, Cincotta, 2008). Gabapentin is reported to produce more sedation but less dry mouth than amitriptyline (Mao, Chen, 2000).


Confusion and weight gain are other less common effects of gabapentin (Mao, Chen, 2000). Ataxia and other movement disorders have been reported and appear to cease when the drug is discontinued (Buetefisch, Guiterrez, Gutmann, et al., 1996; Reeves, So, Sharbrough, et al., 1996). The most commonly reported adverse gabapentin effects in surgical patients are nausea, sedation, dizziness, and urinary retention (Tiippana, Hamunen, Kontinen, et al., 2007).


As mentioned, a major benefit of gabapentin is that it is not hepatically metabolized. This results in minimal drug-drug interactions and hepatic adverse effects. The drug is excreted entirely by the renal system. Gabapentin toxicity was reported in a case describing its use during an episode of acute renal failure (Miller, Price, 2009). The importance of recognizing the need to adjust the dose downward during acute illness, particularly when there is a decline in renal clearance, must be recognized. (See gabapentin patient medication information, Form V-7 on pp. 771-772, at the end of Section V.)



Pregabalin


Pregabalin also has a low adverse effect profile and is well tolerated (Gajraj, 2007). As with gabapentin, dizziness and somnolence are common, and these are typically dose related, transient, and mild to moderate in severity (Gajraj, 2007; Arnold, Russell, Diri, et al., 2008; Lyseng-Williamson, Siddiqui, 2008). Pregabalin has a documented low risk for blurred vision. Patients should be told to report this to their health care provider should it occur. Weight gain also has been noted.


Also, like gabapentin, pregabalin does not undergo hepatic metabolism and has no reported drug interactions of concern (Frank, Cousins, 2008). Additive pharmacodynamic effects of the type that may occur whenever two or more centrally-acting drugs are taken also occurs during pregabalin dosing; patients may report effects on cognitive and gross-motor function when the drug is co-administered with other drugs or alcohol (Blommel, Blommel, 2007). Being a relatively new drug, evaluation of the impact of its adverse effects in older patients requires further research and clinical experience (Guay, 2005). (See pregabalin patient medication information, Form V-11 on pp. 779-780, at the end of Section V.)



Oxcarbazepine


Oxcarbazepine has a better adverse effect profile and is better tolerated than the older anticonvulsants, such as carbamazepine (Jensen, 2002). Rare cases of anaphylactic reactions and angioedema resulted in postmarketing labeling changes for oxcarbazepine (U.S. FDA, 2007b). The drug should be discontinued permanently should these occur. Potentially serious skin reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis, have been reported with the use of oxcarbazepine and also require prompt discontinuation of the drug (Lacy, Armstrong, Goldman, et al., 2008). Hyponatremia should be recognized as a rare adverse effect of this drug, and other effects, such as edema, diplopia, abnormal gait, cognitive slowing, and speech difficulties, have been noted (Guay, 2005; Lacy, Armstrong, Goldman, et al., 2008).




Other Second-Generation Anticonvulsants


Other second-generation anticonvulsant drugs also are usually well tolerated but present a range of potential toxicities (Walia, Khan, Ko, et al., 2004). As noted, all of these drugs can produce the spectrum of adverse effects common to centrally-acting agents, including dizziness, cognitive slowing, mood change, and related experiences. Other adverse effects are more specific to one or another of the drugs. Felbamate, for example, has been associated with rare fatal aplastic anemia and liver failure, which has limited its use to patients with refractory epilepsy. It is generally not considered for neuropathic pain. Lamotrigine has been associated with a relatively high incidence of serious cutaneous hypersensitivity, both Stevens Johnson syndrome and toxic epidermal necrolysis (Lacy, Armstrong, Goldman, et al., 2008). The dropout rate in a clinical trial of zonisamide was high due to a variety of causes including irritability, insomnia, metallic taste, and rash (Atli, Dogra, 2005).



Carbamazepine


Carbamazepine commonly causes sedation, dizziness, nausea, and unsteadiness. These effects can be minimized by low initial doses and gradual dose titration. The intensity diminishes in most patients maintained on the drug for several weeks. Of much greater concern, carbamazepine may cause aplastic anemia, agranulocytosis, or thrombocytopenia in a very small percentage of patients (Hart, Easton, 1982). Therefore, it is critical to obtain a complete hematologic profile prior to therapy, after several weeks, and every 3 to 4 months thereafter. A leukocyte count less than 4000 is usually considered to be a contraindication to treatment, and a decline to less than 3000 (or an absolute neutrophil count of less than 1500) during therapy should lead to discontinuation of the drug. Patients need to be told to report any signs or symptoms of infection, easy bruising, or fatigue.


Other extremely rare adverse effects of carbamazepine include hepatic damage and hyponatremia caused by inappropriate secretion of antidiuretic hormone (Van Amelsvoort, Bakshi, Devaux, et al., 1994). Liver and renal function tests should be routinely evaluated at the start and during the course of therapy. Treatment with carbamazepine may be complicated in older patients who are at risk for cardiac disease, water retention, decreased osmolality, and hyponatremia (Jensen, 2002). Balancing adverse effects with optimal effects in this population can be challenging. Careful monitoring during therapy is recommended.

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Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Adjuvant Analgesics for Persistent (Chronic) Neuropathic Pain

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