Gabapentin in Pain Management (2000)

Gabapentin [1-(aminomethyl)cyclohexane acetic acid]is a structural analog of γ-aminobutyric acid (GABA), which was initially introduced in 1994 as an antiepileptic drug (AED), particularly for partial seizures. For a long time, AEDs such as carbamazepine have been recognized as adjunctive drugs for treating certain symptoms of chronic pain syndromes. It is then not surprising that gabapentin was soon found to be promising in treating neuropathic pain associated with postherpetic neuralgia (PHN) (1,2), postpoliomyelitis neuropathy (3), and reflex sympathetic dystrophy (4). Placebo-controlled clinical trials also have indicated a role of gabapentin in treating pain related to diabetic neuropathy (DNP) (5) and PHN (6). A number of animal studies have investigated the effect of gabapentin on signs of neuropathic pain, such as hyperalgesia and allodynia. Data derived from these studies are generally in agreement with clinical observations. More recently, studies on animal models of acute pain have indicated a role of gabapentin in ameliorating pain from incisional injury and arthritis (7,8), implicating even broader use of gabapentin in treating a variety of pain states. Indeed, it is a common experience that gabapentin has been increasingly prescribed by pain specialists, neurologists, primary care physicians, and other physicians for cases in which pain of nonnociceptive origin is suspected. The clinical impression that there are fewer side effects of gabapentin often becomes part of the rationale for initiating gabapentin therapy. However, both the efficacy and indications of gabapentin for pain treatment are yet to be established, and there is a lack of consensus with regard to the dosage, indications for use of gabapentin, and clinical outcome data. In this article, three lines of evidence will be examined regarding the role of gabapentin in pain treatment: 1) clinical evidence (case reports and trials) for a role of gabapentin in pain treatment will be discussed with an attempt to identify pain symptoms that are likely to be responsive to gabapentin; 2) animal studies of gabapentin on neuropathic pain and other pain behaviors will be evaluated; and 3) possible mechanisms of gabapentin actions will be considered in relation to mechanisms of neuropathic pain in particular. Finally, clinical issues of gabapentin treatment will be discussed in the context of its role in neuropathic pain relief. Clinical Data Thus far, information pertaining to the effectiveness of gabapentin in pain relief is mainly derived from anecdotal case reports. Several open-label, nonplacebo-controlled clinical studies have been conducted. Two randomized, placebo-controlled clinical trials investigated the effect of gabapentin on pain from DNP and PHN. Postherpetic Neuralgia Gabapentin (900 mg/daily) was first reported to be beneficial in a 77-year-old female patient with burning pain in the right T4 dermatome three months after acute herpes zoster infection (1). Similar results of decreased PHN pain with gabapentin were shown in several case reports (2,9), including a retrospective case review (10). In 1998, a randomized, controlled clinical trial investigated the effect of gabapentin on PHN pain (6). In this clinical trial, patients with PHN pain were randomized into gabapentin (n = 113) and placebo (n = 116) groups. During the eight-week trial period, patients in the gabapentin group (a maximum daily dose of 3600 mg) reported a reduction of the daily pain score (0–10 scale) from 6.3 to 4.2 as compared with a half point reduction (from 6.5 to 6.0) in the placebo group. In addition, patients treated with gabapentin also showed some improvement in sleep, affective measures of pain, and quality-of-life outcome measures (6). However, it is not clear whether the improvement in sleep and quality of life is related to the direct effects of medication or secondary to the reduction of pain. One caveat concerning this clinical trial is that tricyclic antidepressants (TCAs) and/or opioids were not discontinued in those patients who were receiving a stable dose range of these co-medications before beginning gabapentin treatment (6). Because both opioids and TCAs are effective in reducing PHN pain (11,12), this design makes it difficult to determine the effect of gabapentin alone on PHN pain. Particularly, the study did not provide information about how many patients in the trial received both gabapentin and co-medications. Thus, the data do not necessarily establish a causal relationship between gabapentin and PHN pain reduction, although the trial indicates a favorable outcome in PHN patients treated with gabapentin. Gabapentin could have its effect on PHN pain via interacting with the effect of TCAs and/or opioids, because gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test (13). Nonetheless, this study suggests that gabapentin is likely to be helpful in reducing PHN pain symptoms. Diabetic Neuropathy Pain associated with DNP was responsive to gabapentin in both case reports (2,14,15) and controlled clinical trials (5,16). In a multi-center randomized (gabapentin 84 subjects; placebo 81 subjects), placebo-controlled trial, monotherapy with gabapentin (a maximum dose of 3600 mg/day), except for the addition of acetaminophen, aspirin, or serotonin reuptake inhibitors as indicated, was shown to reduce DNP pain from 6.4 to 3.9 (0–10 scale), as compared with 6.5 to 5.1 in the placebo control group (5). The data also showed a favorable outcome of gabapentin in improving sleep disturbance and quality of life in patients with DNP pain. It should be noted that global pain scores were used in both DNP and PHN trials (5,6), and no information was generated regarding the effect of gabapentin on individual pain symptoms such as allodynia (nociceptive responses to innocuous stimulation) and hyperalgesia (exaggerated nociceptive response to noxious stimulation). Multiple Sclerosis (MS) Several case reports have shown a reduction of pain associated with MS (17–20). In two open-label, nonplacebo-controlled clinical studies (18,20), gabapentin (up to 1200 mg/day) was found to be helpful in reducing several types of pain in MS patients. Such pain conditions include painful tonic spasms and dysesthetic or paresthetic symptoms. In general, gabapentin treatment appears to be more effective in reducing paroxysmal pain with throbbing, pricking, and cramping quality than dull aching pain in MS patients. These findings suggest that a large-scale, controlled clinical trial may be warranted to determine the effectiveness of gabapentin in improving pain in MS patients. Neuropathic Cancer Pain In an uncontrolled clinical study (21), gabapentin was added to the opioid treatment regimen in 22 cancer patients whose pain was only partially responsive to opioid treatment. It was found that pain decreased from 6.4 to 3.2 (0–10 scale) at one to two weeks after the addition of gabapentin. In particular, burning pain was decreased from 5.1 to 2.0 and daily episodes of shooting pain from 7.2 to 2.2. Allodynia also disappeared in seven of nine patients after the addition of gabapentin into the treatment regimen. Although a number of variables including opioid doses and other co-medications were not controlled in this clinical observation, the data seem encouraging for those cancer patients suffering from intractable neuropathic pain. Miscellaneous Case Reports Sporadic case reports suggest that gabapentin may be effective in reducing pain associated with reflex sympathetic dystrophy (4), erythromelalgia (22), idiopathic trigeminal neuralgia (23), peripheral neuropathy (24,25), postthoracotomy neuropathy (26), central pain syndromes (27,28), Guillain-Barre syndrome (29), and taxane-induced myalgias (30). Information from these case reports suggests that neuropathic pain with lancinating and steady-burning quality is more likely to respond to gabapentin as compared with pain of other qualities. An important issue unaddressed in the aforementioned clinical trials and case reports is the effectiveness of gabapentin in attenuating individual symptoms of neuropathic pain. In an open-label, nonplacebo-controlled clinical study (31), effects of gabapentin on both spontaneous and stimulation-evoked pain were investigated in 18 patients with either peripheral or central neuropathic pain. Responses to stimulation-evoked pain were detected by using the quantitative sensory tests, which included the use of mechanical (von Frey filaments) and thermal (a contact thermode) stimulation. It was found that, at a maximum dose of 2400 mg/day, gabapentin moderately reduced spontaneous pain, particularly spontaneous paroxysmal pain. Both tactile and cold allodynia were reduced by gabapentin treatment. However, gabapentin did not change pain thresholds to either mechanical or thermal (hot) stimulation, and it did not reduce mechanical and thermal hyperalgesia. Several points may be mentioned from the currently available clinical data. First, except for a few randomized, controlled clinical trials, most information regarding the efficacy of gabapentin on pain relief has been derived from anecdotal clinical observations. Second, gabapentin appears to be helpful in reducing spontaneous, paroxysmal pain with burning and lancinating quality as well as allodynia to cold and tactile stimuli. Dull, aching pain and hyperalgesia are less likely to be responsive to gabapentin treatment. It is, however, not conclusive based on these reports 1) how extensively gabapentin is being used in the clinical practice and 2) how effectively gabapentin treatment relieves pain conditions. Third, a common dosing schedule from these reports involves an initial dose of 100–300 mg/day and a gradual dose escalation (100–300-mg increment every two-three days) up to a maximal tolerable dose of 2700–4800 mg/day. Fourth, the limited clinical data suggest that pain symptoms, rather than the etiology of pain symptoms, are likely to be a predictive factor for a positive response to gabapentin treatment. (See Table 1 for a summary of clinical trial data.)Table 1: Summary of Clinical Trial DataPreclinical Data A major advantage of preclinical trials is that the effect of gabapentin can be differentially examined on individual signs of neuropathic pain such as allodynia, hyperalgesia, and spontaneous pain. A number of animal studies have been performed in the last several years. The data from these studies are summarized below based on the effect of gabapentin on nociceptive thresholds, allodynia, and hyperalgesia. Nociceptive Thresholds Consistent with human studies that indicate no changes in nociceptive thresholds by gabapentin (31), gabapentin did not alter nociceptive thresholds in animal models of neuropathic pain (32), acute arthritic pain (8), formalin-induced nociception (33,34), or thermal injury (35). Interestingly, gabapentin has been reported to facilitate responses of spinal cord dorsal horn neurons to noxious C fiber and Aδ fiber, but not Aβ fiber, stimulation in normal rats (36). In sharp contrast, gabapentin dose-dependently reduced dorsal horn neuronal responses to C fiber, but not Aβ fiber, stimulation in inflammatory rats three days after the carrageenan injection (36). A similar effect of gabapentin was shown in an animal model of selective nerve root (L5 and L6) ligation (37). These findings suggest 1) a differential effect of gabapentin in normal and inflammatory pain states, 2) a selective effect of gabapentin on spinal cord neuronal responses to noxious (Aδ and C fiber) versus innocuous (Aβ fiber) peripheral stimulation, and 3) an adverse (facilitatory) effect of gabapentin on nociceptive responses of spinal cord dorsal horn neurons in the absence of pathological pain states. Allodynia Allodynia to tactile or thermal stimuli could be elicited in animals with nerve injury (32,38,39), incisional injury (7), diabetes (40), and abnormal immunoresponses to anti-GD2 ganglioside (41). Gabapentin given systemically reduced mechanical and/or cold-induced allodynia in each of these animal models. The gabapentin-related compound pregabalin also reduced mechanical allodynia in diabetic rats (40). Three observations from these studies are worth mentioning: 1) the antiallodynic dose of gabapentin did not affect nociceptive thresholds (32); 2) although lamotrigine (an AED) and gabapentin both decreased cold allodynia in rats with nerve injury, only gabapentin also decreased mechanical allodynia in these same rats (32); and 3) although systemic morphine or amitriptyline blocked static mechanical allodynia (von Frey filament stimulation) in diabetic rats, gabapentin or pregabalin dose-dependently blocked both static and dynamic (lightly stroking the skin with a cotton bud) mechanical allodynia in the same rat model (40). These observations are consistent with a clinical study that indicates a selective reduction of allodynia by gabapentin (31). Hyperalgesia Both thermal and mechanical hyperalgesia have been shown to be reduced by systemic or intrathecal gabapentin in animal models of incisional injury (7), peripheral nerve injury (42), thermal injury (35,43), substance P-induced hyperalgesia (44), and acute arthritis (8). Pretreatment with gabapentin also blocked the development of hyperalgesia, suggesting a preventive effect of gabapentin (7,8,43). The antihyperalgesic effect of gabapentin is likely to be mediated at a central site, because intrathecal gabapentin injection produced an effect similar to that of systemic gabapentin administration (8,35). It should be noted that, unlike the results shown in the animal studies, both mechanical and thermal hyperalgesia were unchanged by gabapentin in patients with neuropathic pain, as assessed by quantitative sensory tests (31). Subcutaneous injection of formalin into a rat’s hind paw elicits a two-phase response (45). This two-phase response is unique in that the first phase (Phase 1) is related to a normal (physiological) nociceptive process, whereas the second phase (Phase 2) may reflect a hyperalgesic condition involving a state of central sensitization. Except for one study that reported a moderate reduction of Phase 1 nociceptive behaviors by systemic gabapentin (46), gabapentin given either systemically or intrathecally reduced hyperalgesic behaviors only in Phase 2 of the formalin test (33,34,46,47). Coadministration of gabapentin and formalin into the rat’s hind paw itself also reduced Phase 2 hyperalgesic behaviors (48). In summary, the present laboratory studies indicate that 1) gabapentin does not affect nociceptive thresholds, 2) gabapentin is effective in reducing both allodynia and hyperalgesia in animal models, and 3) gabapentin may have a selective effect on the nociceptive process involving central sensitization. Among these findings, evidence suggesting an antiallodynic effect of gabapentin and the lack of effect on nociceptive thresholds is consistent with that seen in clinical studies. No data are available with regard to the effect of gabapentin on spontaneous pain in animal models. Potential Mechanisms of Gabapentin Actions Neuropathic pain is characterized by distinctive clinical symptoms and signs such as spontaneous pain, allodynia, hyperalgesia, and pain summation. Neuropathic pain is often considered to be poorly responsive to conventional analgesic medications, including nonsteroid antiinflammatory drugs and opioid analgesics. Both peripheral and central mechanisms of neuropathic pain have been proposed (49,50). Peripherally, abnormal activation of sodium channels leading to the generation of ectopic discharges is likely to be attributable to symptoms of neuropathic pain, particularly spontaneous, paroxysmal pain. Centrally, sensitization of spinal cord dorsal horn neurons in response to abnormal, repetitive peripheral nociceptive input after nerve/tissue injury plays a significant role in both development and maintenance of neuropathic pain symptoms. A key process of this central sensitization is the activation of N-methyl-d-aspartate (NMDA) receptors by glutamate/aspartate within the central nervous system. In addition, an imbalance between the spinal cord inhibitory and excitatory circuitry, presumably the result of a decreased spinal cord inhibitory (GABA) influence, may also contribute to a central hypersensitization state. Perplexingly, actions of gabapentin on pain relief do not seem to interact with any of these known mechanisms. Gabapentin is ineffective in blocking sodium channel-mediated repetitive action potentials in cultured neurons (51). Consistent with this in vitro observation, both conduction velocity and responses of Aδ- and C-afferent fibers to noxious mechanical stimulation were not changed by gabapentin in normal rats (39). However, IV gabapentin (30–90 mg/kg) dose-dependently suppressed ectopic discharges in rats with partial sciatic nerve ligation (39). The gabapentin dose range effective for suppressing ectopic discharges is equivalent to that for reducing mechanical allodynia in the same rat model (39). These findings would suggest a selective blockade of nerve injury-induced ectopic discharges by gabapentin, an effect similar to that after systemic In contrast, gabapentin mg/kg) given systemically to reduce ectopic discharges in a rat model of selective nerve root although the same dose of gabapentin was effective in attenuating mechanical allodynia The results from this study a peripheral effect of gabapentin on allodynia. Gabapentin is a structural analog of which the given systemically however, does not to receptors Although gabapentin may the and of it does not affect the and of the antiallodynic effect of gabapentin is not by of receptors It is that the antiallodynic effect of gabapentin, as shown in animal studies, is by an of the inhibitory (GABA) via its direct with receptors or its effect via The is a of a and several including a is an for the The antihyperalgesic effect of gabapentin has been shown to be by in animal models of formalin-induced nociception substance and hyperalgesia (44), and thermal injury (35). These data would suggest that gabapentin as an at the site, and gabapentin the gabapentin However, studies to any between gabapentin and the including the In the absence of it is that gabapentin has its effect by of interacting with the A was initially in the central nervous This was as the of channels gabapentin, but not to this It has been proposed that gabapentin hyperalgesia by to this common site, because but not similar antihyperalgesic effects Although channels have been in hyperalgesia it is difficult to that to channels alone by gabapentin would for its effects on allodynia and hyperalgesia in animal studies. In addition, the of gabapentin in blocking channels is not In particular, the dose of gabapentin used in the clinical is several than that of mechanisms of gabapentin on pain relief Gabapentin does not interact with and Although gabapentin this action is to be attributable because the blockade of receptors does not change the effect on allodynia. A peripheral of gabapentin on abnormal sodium activation has been but the data A of has been for gabapentin and However, a causal relationship between this and pain relief is yet to be studies some in the reduction of hyperalgesia between gabapentin and Such results would suggest that the of channels would be the to the development and maintenance of hyperalgesia. Thus far, information is available to this Clinical Gabapentin Pain of nonnociceptive origin including neuropathic pain is a daily both to patients and who to pain treatment that provide beneficial in patients with such intractable pain will be a addition to the pain treatment Indeed, gabapentin has been as a promising drug in pain although it was initially by the and as an adjunctive drug for partial However, several clinical issues of gabapentin should be to a use of this drug in pain These issues include the efficacy and side effect and between gabapentin and other currently available pain Gabapentin an Data from both preclinical and clinical studies that gabapentin does not change nociceptive Thus, gabapentin is to be a conventional analgesic opioids that by of nociceptive No evidence gabapentin to be effective in reducing nociceptive pain. regard to neuropathic pain, the two controlled clinical trials a but significant reduction of global pain scores in patients with DNP and PHN. These two trials, however, used global pain scores and did not the effect of gabapentin on individual pain symptoms such as spontaneous pain versus stimulation-evoked pain in DNP and PHN patients. In addition, these two trials did not the effects of gabapentin on of and clinical studies a role of gabapentin in reducing spontaneous pain and allodynia to both thermal and mechanical stimuli of the Gabapentin appears particularly helpful in reducing paroxysmal pain with lancinating and burning quality in these studies. It whether gabapentin is effective in attenuating hyperalgesia. of the information regarding gabapentin in treating neuropathic pain from case reports with a limited number of patients. gabapentin is extensively used for chronic pain conditions mainly based on these anecdotal reports. One of case reports is that favorable clinical are reported clinical Thus, the of these case reports should be by controlled clinical Gabapentin than Pain Gabapentin is considered to be with fewer side effects and with other In an the and of gabapentin in treatment were investigated in two of patients receiving a daily dose of either or This study that the was in patients receiving more than mg/day of gabapentin than those receiving mg/day, a result a regard to the of the reported at one of the adverse and A of of discontinued the gabapentin secondary to adverse The study did not the and of gabapentin with other used and it did not provide the outcome of reduction in relation to the of adverse Similar side effects have been in pain patients treated with gabapentin. The major side effects related to gabapentin treatment include and are case reports of and Thus far, only one study compared the side effect of gabapentin and a used adjunctive pain medication This study to a side effect of gabapentin A of and was in the gabapentin a of was seen in the amitriptyline group. in both the side effects and in pain relief. Gabapentin than Pain Although it is difficult to the efficacy of medications, the of one medication the other should include the of outcome side effect and there is only one randomized, study that compared the efficacy of gabapentin and amitriptyline on DNP pain pain relief was reported in of patients treated with gabapentin (a daily dose of mg) and of with amitriptyline (a daily dose of This clinical trial to an effect of gabapentin One caveat concerning this clinical trial is that no on individual symptoms of DNP pain were between gabapentin and amitriptyline Thus, it is not clear whether gabapentin would be more effective than amitriptyline in ameliorating neuropathic pain with a certain such as burning pain and spontaneous, paroxysmal pain. The side effect do not between these two as discussed is, however, a between a of gabapentin with the dose range of mg/day) and the amitriptyline and In summary, gabapentin has been shown to be effective in reducing neuropathic pain associated with and neuropathic pain. Gabapentin appears to be helpful in reducing spontaneous, paroxysmal pain with burning and lancinating quality as well as allodynia to cold and tactile stimuli. Dull, aching pain and hyperalgesia are less likely to be responsive to gabapentin treatment. The results from preclinical studies are generally consistent with clinical In particular, both clinical and preclinical trials have shown an antiallodynic effect of gabapentin and a lack of effect on nociceptive Although gabapentin was effective in certain neuropathic pain symptoms, clinical trials should be performed to the efficacy of gabapentin. For the effect of gabapentin on symptoms and signs of neuropathic pain should be assessed in patients with neuropathic pain. more data are to the that gabapentin is the treatment for neuropathic pain with a fewer side and a favorable