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Pregabalin for the management of neuropathic pain in spinal cord injury
Practice Points
Kevin L Dalal1, Elizabeth R Felix1,2 & Diana D Cardenas*1,2 Pregabalin is used as a nonopioid analgesic for the treatment of a variety of conditions, most recently
approved by the US FDA in the management of neuropathic pain associated with spinal cord injury. Start initially with 150 mg/day in divided doses two-times a day and assess for adverse events. May
titrate up to 300 mg/day within the first week and adjust upward weekly to a maximum of 600 mg/day in divided doses as tolerated. Abrupt or rapid cessation may result in insomnia, nausea, headache, anxiety, hyperhidrosis and diarrhea.
Patients with seizure disorders may experience increased seizure frequency if pregabalin is rapidly discontinued. Taper pregabalin gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Improvement in pain, in patients with spinal cord injury, can be seen as early as 1 week. To fully
evaluate the efficacy of the medication, it is recommended that administration continue for a period of 4–6 weeks, assuming tolerability of adverse reactions. Adverse events associated with the use of pregabalin are evident in the initial weeks of administration
and may dissipate with continued use. Among these events, the most common are dizziness, somnolence, dry mouth, fatigue, lower extremity edema and weight gain. Angioedema is a rare adverse reaction, but may occur during initial or chronic use of pregabalin and
requires emergency treatment and immediate discontinuation of drug. The treatment of neuropathic pain may not be effectively accomplished with a single medication or
even a combination of medications, and other nonpharmacological treatments may be helpful. If a combination of medications is used, pregabalin can be safely combined with tricyclic medications, other antiepileptic medications, NSAIDs and even opiates. The effect of combination therapies has not been thoroughly studied in neuropathic pain in spinal cord injury, but there should be caution if combining pregabalin with angiotensin-converting enzyme inhibitors as there is an increased risk of angioedema.
Department of Rehabilitation Medicine, University of Miami Miller School of Medicine, Miami, FL, USA Research Service, Department of Veterans Affairs Medical Center, Miami VA Healthcare System, Miami, FL, USA *Author for correspondence: [email protected] 1 2
10.2217/PMT.13.35 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(5), 359–367
part of
ISSN 1758-1869
359
REVIEW Dalal, Felix & Cardenas SUMMARY Pregabalin is the only US FDA-approved drug to date for neuropathic pain in spinal cord injured patients. Pregabalin is a novel GABA analog whose primary mechanism of action involves binding at the a2-d subunit of voltage-sensitive calcium channels. Efficacy is noted within the first several days of administration. Dosing is typically initiated at 150 mg/day in divided doses, but may be started at even lower doses. Dosing can be increased gradually to a recommended maximum of 600 mg per day in divided dosing. Adverse events include somnolence, dizziness and dry mouth, and typically manifest within the first 2 weeks of treatment. Pregabalin is generally safe to use in combination with other pain medications or antidepressants, but safety in pregnant patients has not been established. Background Pregabalin is used as a nonopioid analgesic for the treatment of a variety of conditions, most recently approved by the US FDA for the management of neuropathic pain associated with spinal cord injury. Neuropathic pain affects between 3 and 8% of the world’s population as a whole, and can impact various aspects of a patient’s functional abilities and quality of life [1]. Within the realm of spinal cord injury, neuropathic pain affects approximately 40% (100,000) of the 270,000 patients with spinal cord injury in the USA [1]. It emerges early in the postinjury period and may persist chronically for decades. Severe cases can significantly hinder the patient’s potential for rehabilitation and functional recovery. Neuropathic pain is thought to occur after sensory neuron damage, which leads to disorganized axonal sprouting and neuroma formation. These alterations in the nerve architecture consequently alter voltage-gated channel expression. Although the mechanism of action is not precisely known, it is believed that pregabalin is able to inhibit neuronal hyperactivity traveling along these pain pathways by selectively binding the Ca 2+ a2-d subunit in the CNS. This in turn reduces calcium flow through the channel, thus reducing neurotransmitter release from the presynaptic neuron. Hence, transmission is reduced, and nociceptive signaling is reduced [2]. Indications & usage
Pregabalin was recently approved, as of June 2012, by the FDA for the treatment of neuropathic pain associated with spinal cord injury [101]. To date, pregabalin is the only medication approved for this indication in spinal cord injury (SCI). So far, the FDA has approved five indications for treatment by pregabalin. Prior to its approval for neuropathic pain in SCI, other indications included: neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia and as adjunctive therapy for adult patients
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with partial-onset seizures [102]. Pregabalin is a structural derivative of the inhibitory neuro transmitter GABA. However, it does not bind directly to GABA-A, GABA-B or benzodiazepine receptors, nor does it augment GABA-A response in cultured neurons. Furthermore, pregabalin does not augment GABA-A responses in cultured neurons, alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter proteins and increases the rate of functional GABA transport [102]. Initially, the FDA approved pregabalin for the treatment of pain associated with diabetic peripheral neuro pathy and postherpetic neuralgia, becoming the first medication approved in both Europe and the USA to treat both of these conditions [2]. Shortly thereafter, pregabalin was approved as an adjuvant medication in the treatment of partial-onset seizures [2]. Pregabalin’s structuraly related predecessor in the treatment of neuropathic pain is gabapentin. Gabapentin has also been shown to be effective in treating neuropathic pain in SCI and was originally designed as a GABA-mimetic agent that freely crosses the blood–brain barrier [3]. A review of multiple studies examining the use of gabapentin or pregabalin in the treatment of neuropathic pain in SCI suggested that pregabalin was more efficacious in several measures when compared with gabapentin, and both medications had a better tolerability and safety profile than either opioids or tricyclic antidepressants [3]. Despite being considered as antiepileptic medications, some emerging predominant indications for use besides neuropathic pain include fibromyalgia and generalized anxiety disorder. As of 2008, 40% of pregabalin sales were for the indication of neuropathic pain [4]. One common denominator between epilepsy and such nonepileptic disorders is altered neuronal excitability caused by abnormally functioning membrane
future science group
Pregabalin for the management of neuropathic pain in spinal cord injury ion channels [1]. However, the utility of antiepileptic drugs, such as pregabalin, in treating other neurologic and psychiatric disorders is due to a combination of factors; included among these are multiple mechanisms of action, diverse efficacy, low potential for interactions and favorable tolerability profile. In 2007, pregabalin became the first medication to be FDA approved for the treatment of fibromyalgia [5]. Despite a constellation of symptoms, pain associated with fibromyalgia is ranked by clinicians and patients as having the greatest impact on quality of life in this patient group [5]. Dosage & administration
Although there may be variations in different countries, in the USA, pregabalin is available as an oral solution containing 20 mg/ml, and as capsules in 25, 50, 75, 100, 150, 200, 225 and 300 mg. The recommended initial dosing for all indications is 150 mg/day, which may be increased based on efficacy and tolerability. Depending on the indication, pregabalin is given in divided doses, either two-times a day for fibromyalgia or neuropathic pain associated with SCI, or three-times daily for painful diabetic neuropathy. Pregabalin can be given two-times a day or three-times daily for postherpetic neuralgia, or as adjunctive therapy for adults with partial-onset seizures. For all indications, the dose may be increased to 300 mg/day within 1 week, based on efficacy and tolerability. For fibromyalgia, neuropathic pain associated with SCI and postherpetic neuralgia, pain relief may not be achieved until higher doses are reached. Studies show therapeutic results at dosing as high as 600 mg total per day for postherpetic neuralgia and neuropathic pain associated with SCI. Because pregabalin is eliminated primarily by renal excretion, the dose in patients with reduced renal function should be adjusted [102]. Some resources recommend a maximum dose of pregabalin at 100 mg three-times daily (300 mg/day) in patients with creatinine clearance of at least 60 ml/min. Supplemental dosing may be considered immediately following hemodialysis [6]. A review article discussing studies from 1993 to 2005 showed that there was not a significant difference between dosing at 75 mg/day versus placebo in patients with neuropathic pain due to various etiologies [6]. By the end of the first week, efficacy could be detected. Maximum efficacy was typically reached at a specific dose within the first week of its administration. Dosing between
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300 and 600 mg/day was shown to significantly reduce neuropathic pain in postherpetic neuralgia and diabetic neuropathy. Clinical pharmacology Mechanism of action
Pregabalin is a novel GABA analog whose primary mechanism of action involves binding at the a2-d subunit of voltage-sensitive calcium channels [7]. Binding decreases calcium influx through the calcium channels, leading to a reduction in the release of several neurotransmitters, including glutamate, substance P and noradrenaline [8]. Pregabalin, thus, has a modulating effect on the release of specific neurotransmitters that are implicated in neuropathic pain, partial seizures and anxiety [6]. Although pregablin is a chemical analog of GABA, the drug has no GABA-ergic activity. When compared with gabapentin, a drug with a similar mechanism of action, pregabalin is more potent than gabapentin and has a threefold greater rate of absorption [9]. In a recent study of persons with neuropathic pain and SCI using magnetic resonance spectroscopy, reduced metabolite concentrations in the anterior cingulate cortex of glutamate– glutamine/inositol ratios were found in those with severe neuropathic pain and a significant psychosocial impact [10]. In a recent randomized controlled crossover study of pregabalin versus placebo in persons with fibromyalgia, reduced concentrations of glutamate–glutamine/creatinine in the posterior insula were found, suggesting that these changes may be related to its mechanism of action [11]. Further research in humans is needed to determine whether pregabalin alters glutamate–glutamine and other brain metabolites in persons with SCI and neuropathic pain. Pharmacokinetics
Pregabalin is administered orally and readily absorbed into the blood stream reaching a peak concentration within 1 h [9]. Absorption occurs within the small intestine and the ascending portion of the colon [12]. The blood concentration in healthy subjects has a linear relationship over a dose range of 75–900 mg per day [13]. It has not been determined whether this linear relationship holds for persons who have a neurogenic bowel, such as spinal cord-injured patients. The bioavailability of pregabalin is high, averaging ≥90% in healthy subjects [14]. Agents that reduce small bowel motility are not expected to have a significant effect on the absorption of pregabalin.
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REVIEW Dalal, Felix & Cardenas Only the rate of absorption is affected by food so it can be taken with or without food [14]. After oral ingestion, pregabalin is found in the blood as well as in the cerebrospinal fluid, although the peak cerebrospinal fluid concentration occurs at 8 h in healthy subjects. The half-life of pregabalin is approximately 6 h. Pregabalin is not bound to plasma proteins nor does it inhibit CYP450 enzymes. Renal excretion is the primary pathway for elimination, necessitating dose adjustments for those with impaired renal function, as discussed previously [15]. Clinical evidence Overview of clinical trials
To evaluate the literature related to the treatment of neuropathic pain in persons with SCI, PubMed and CINAHL were searched using the terms ‘pregabalin’ or ‘Lyrica’ and ‘spinal cord injury’ ‘spinal cord injuries’, or ‘SCI’. These searches yielded a total of 27 publications: five articles of clinical trials or case studies related to the effectiveness and/or side effects of pregabalin for the treatment of neuropathic pain in persons with SCI; one case study related to pregabalin for treatment of prurigo in a patient with SCI; 11 review articles; six articles using rodent models of SCI; two articles measuring outcomes not related to pain; one clinical trial for a drug other than pregabalin; and one comment on a previously published article. Review of these articles revealed two published randomized, double-blind controlled studies that have specifically investigated the efficacy of pregabalin in adult subjects (≥18 years old) with below-level central neuropathic pain associated with SCI [16,17]. One additional clinical trial has reported on the efficacy of pregabalin in a sample of subjects with central neuropathic pain of different etiologies, with a majority (52.5%) of subjects having central neuropathic pain due to SCI [18]. Details regarding subject selection, methods and results for each of these studies are shown in Table 1. The two large studies performed exclusively in persons with SCI included data from 137 and 220 subjects, over a 12- and 16-week treatment period, respectively [16,17]. The Siddall et al. study was performed in eight sites in Australia [16], while the Cardenas et al. study included 60 sites in ten countries in North America, South America, Asia and Europe [17]. Similar inclusion criteria were used in both studies: tetraplegic and paraplegic patients, with either incomplete or complete SCIs, who had
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chronic neuropathic pain (continuously for the past 3 months or relapsing and remitting for the past 6 months) that was rated an average of at least 4 on a 0–10 numerical rating scale of pain intensity. Both studies also allowed patients to continue other stable analgesic regimens, with the exception of gabapentin or pregabalin. Those who were taking gabapentin or pregabalin were required to discontinue at least 1 week prior to study entry. All three studies that have included SCI patients with central neuropathic pain utilized a dose escalation protocol, with dosing starting at 150 mg/day and increasing to a maximum of 600 mg/day, dependent on efficacy and tolerability in each subject [16–18]. Average stabilized dose was reported as 460 mg/day in the Siddall et al. study [16], and 410 mg/day in the Cardenas et al. study [17]. All studies utilized intention-to-treat analyses, and reported patient flow through the trial, including details regarding subject discontinuation/drop-out. Results from these studies support the effectiveness of pregabalin for reducing central neuro pathic pain associated with SCI. Significant differences in daily pain ratings at the end of the treatment protocol were reported between subjects receiving pregabalin and those receiving an inactive placebo. The small study of mixedpathology (spinal cord and brain injury) central neuropathic pain also found a statistically significant decrease in pain intensity ratings during the final week of a 4-week pregabalin treatment trial [18]. In the Siddall et al. study, the end point mean pain score (average of daily ratings of pain intensity during the final week [week 12] of treatment controlled for baseline ratings of pain intensity) was significantly lower for the pregabalin group (numerical rating scale score = 4.62 ± 2.1; mean ± standard deviation) compared with the placebo group (6.27 ± 2.1) [16]. Similarly, the Cardenas et al. study reported significantly greater duration-adjusted average decrease in numerical pain ratings for the pregabalin group (-1.66 ± 0.16; least squares mean ± standard error) compared with the placebo group (-1.07 ± 0.15) when comparing the 16-week end point with baseline ratings of pain [17]. Both studies also reported that a reduction of pain ratings was apparent within the first week of treatment with pregabalin [16,17]. Using responder analyses, the number needed to treat (NNT), based on 30% pain reduction, was calculated at 3.9 in the Siddall et al. study [16]
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Pregabalin for the management of neuropathic pain in spinal cord injury and seven in the Cardenas et al. study [17], and both studies reported a NNT of seven for 50% pain reduction. Efficacy of pregabalin was also consistent across the two studies for secondary outcome measures, including significantly decreased sleep interference and significantly greater Patient Global Impression of Change ratings for subjects receiving pregabalin compared with those receiving placebo [16,17]. Although the NNT for patients with moderate-to-severe central neuropathic pain associated with SCI appears to be higher than the NNT (3.9) for patients experiencing peripheral neuropathic pain due to diabetic peripheral neuro pathy or postherpetic neuralgia [19], the two published studies in SCI provide class I evidence (blinded, randomized, controlled and adequately powered) for the effectiveness of pregabalin for this notoriously difficult to treat central pain condition [16,17], which resulted in FDA approval of pregabalin for the treatment of neuropathic pain in SCI. Titrated doses of between 300 and 600 mg/day were found to be appropriate for most subjects, and balancing of effective pain reduction with tolerable adverse events on a patient-by-patient basis was suggested. Other clinical evidence
In addition to clinical trial studies of pregabalin for the treatment of neuropathic pain in persons with SCI, a limited number of other publications support the potential efficacy of pregabalin in this patient population. In a sample of 72 patients in the UK who were prescribed pregabalin for pain associated with chronic SCI, measures of compliance and persistence with pregabalin therapy were high, suggesting good efficacy and tolerability for pregabalin in these patients [20]. However, estimates of total medical costs (including costs associated with outpatient, emergency room and hospital visits, and medication and procedure costs) during the 9-month period after initiating treatment with pregabalin were statistically significantly higher compared with the 9-month period preceding the initiation of pregabalin [20]. A case report by Westermann et al. detailed the effect of pregabalin in a patient with chronic SCI and neuropathic pain in the area at the neurological level of injury [21]. Although the patient reported the same symptoms and severity of clinical pain bilaterally, quantitative sensory testing and intraepidermal nerve fiber density testing revealed differences in fiber-density and nerve
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function between the left and right sides of the body in the area of neuropathic pain. Administration of 300 mg/day pregabalin reduced pain intensity on the side of the body with greater residual sensory function from 8 to 2 on a numerical rating scale, but did not reduce reported pain intensity on the other side. The authors suggest that, based on the sensory testing and fiber density results, differences in mechanisms related to neuropathic pain were revealed for different sides of the body in this patient, and that these differences in mechanism were related to the unilateral effectiveness of pregabalin at the dose utilized [21]. Future research should be aimed at investigating whether patients with specific phenotypes or identified mechanisms of neuropathic pain may be more likely to benefit from treatment with pregabalin than other patients. Safety & tolerability Adverse reactions
Pregabalin has been deemed to have a low potential for abuse relative to other drugs in schedule IV, and even in the case of abuse, it has a low potential for physical or psychological dependence relative to this same cohort. Therefore, pregabalin was placed in schedule V by the FDA [22]. Although a majority of SCI subjects taking pregabalin reported at least one adverse event during treatment trials (96 [16] and 67% [17]), a large proportion of subjects taking placebo also reported adverse events (75 [16] and 47% [17]). The severity of side effects was generally mild, with 5 and 21% of subjects in the pregabalin group and 5 and 13% of the placebo group, withdrawing due to adverse events from the Cardenas et al. [17] and Siddall et al. [16] studies, respectively. The most commonly reported side effects of pregabalin were somnolence, dizziness and peripheral edema (Table 1). In addition to these conditions, other adverse events reported by at least 10% of subjects randomized to pregabalin in the Siddall study included: asthenia/loss of strength, dry mouth, constipation and amnesia [16]. No clinically relevant changes in laboratory tests (hematology, chemistry and urina lysis), physical examination or EKG results were reported in either study. Reported incidence of somnolence in SCI subjects taking pregabalin appear to be higher than that reported in other patient populations. Approximately 15–25% of patients with postherpetic neuralgia, and 5–16% of those with diabetic peripheral neuropathy reported
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REVIEW Dalal, Felix & Cardenas Table 1. Randomized controlled trials of pregabalin in persons with neuropathic pain associated with spinal cord injury. Study (year)
Drug
Siddall et al. (2006)
Vranken et al. (2008)†
Subjects n
Design
Results
Average age (years)
Male (%)
Treatment Average dosage, weeks in mg/day (range) trial (n)
Mean difference Subjects with >30% Subjects with in pain rating pain relief (%) >50% pain relief from baseline to (%) end point
Placebo 67 Pregabalin 70
49.8 50.3
81 86
12
– 460 (150–600)
-0.46 -1.92
16 42
8 22
Placebo 20 Pregabalin 20
55 54
50 55
4
– Not reported (150–600)
-0.1 -2.5
10 35
5 35
85 76
16
– 410 (150–600)
-1.07 -1.66
31 46
15 30
Cardenas Placebo 107 45.6 et al. Pregabalin 112 46.1 (2013)
Included patients with central neuropathic pain of both brain and spinal cord etiology. A total of 50% of subjects in the placebo arm were spinal cord injury and 55% of subjects in the pregabalin arm were spinal cord injury. Results presented in this table are for all subjects (spinal cord and brain injury or disease). The authors reported that degree of pain relief during pregabalin treatment did not significantly differ between subjects with spinal cord injury and those with brain injury. EQ-5D: EuroQol instrument 5D; HADS: Hospital Anxiety and Depression Scale; MOS-SS: Medical Outcomes Study Sleep Scale; SF-MPQ: Short Form – McGill Pain Questionnaire; PGIC: Patient Global Impression of Change; VAS: Visual analog scale. †
somnolence during treatment with pregabalin [23–25], compared with between 33 and 41% of those with SCI-related neuropathic pain [16,17]. A comprehensive review including subjects treated with pregabalin for neuropathic pain, epilepsy and generalized anxiety disorder, reported that up to 50% of subjects identified somnolence as an adverse effect in the clinical trials included in the review [6]. It has been suggested that the greater percentage of subjects with SCI reporting somnolence may be due to additional pharma cologic agents taken by SCI subjects, particularly antispasticity/sedating medications that may have additive CNS effects with pregabalin to increase somnolence. The frequency of reports of dizziness in the SCI samples, however, are similar to those reported in other populations (18–24% [16,17] vs 13–35% in postherpatic neuralgia [23,24] and 23% in diabetic peripheral neuralgia [25]), as were reports of peripheral edema (10–12% [16,17] vs up to 16% in diabetic peripheral neuropathy [25] and 19% in diabetic peripheral neuropathy and posteherptic neuralgia studies combined [26]). Weight gain was reported as an adverse event in less than 5% of SCI subjects taking pregabalin [16,17]. However,
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measured weight gain in the pregabalin group was an average of +2.0 kg in the Siddall et al. study [16] and +0.8 kg in the Cardenas et al. study [17], compared with average weight losses of -0.8 kg [16] and -0.4 kg [17] in the placebo groups, and clinically significant weight gain (≥7% increase) was recorded in 11.4% of patients taking pregabalin over 12 weeks (compared with 3.1% of patients taking placebo) [16]. Across clinical trials of pregabalin for a variety of other patient groups, approximately 15% of subjects gain ≥7% of their baseline weight at or approximately 2 months after medication onset [26]. Other, less frequent, adverse outcomes reported are abnormal thinking, asthenia, infection, mouth dryness, diplopia, nervousness, amblyopia, amnesia, diarrhea and incoordination [6]. In summary, the most common adverse events related to pregabalin use for central neuropathic pain in SCI are somnolence, dizziness and peripheral edema. The severity of these events was generally reported as mild or moderate and adverse events led to study withdrawal in only approximately 5–20% of subjects. In addition to these common side effects, some caution should be used when prescribing pregabalin in persons with heart
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Pregabalin for the management of neuropathic pain in spinal cord injury
REVIEW
Table 1. Randomized controlled trials of pregabalin in individuals with neuropathic pain associated with spinal cord injury (cont.). Results (cont.)
Subjects with adverse events (%)
Ref.
Primary outcome summary
Secondary outcome summary
>1 adverse event
Somnolence Dizziness Peripheral edema
Significantly (p
Pregabalin for the management of neuropathic pain in spinal cord injury
Practice Points
Kevin L Dalal1, Elizabeth R Felix1,2 & Diana D Cardenas*1,2 Pregabalin is used as a nonopioid analgesic for the treatment of a variety of conditions, most recently
approved by the US FDA in the management of neuropathic pain associated with spinal cord injury. Start initially with 150 mg/day in divided doses two-times a day and assess for adverse events. May
titrate up to 300 mg/day within the first week and adjust upward weekly to a maximum of 600 mg/day in divided doses as tolerated. Abrupt or rapid cessation may result in insomnia, nausea, headache, anxiety, hyperhidrosis and diarrhea.
Patients with seizure disorders may experience increased seizure frequency if pregabalin is rapidly discontinued. Taper pregabalin gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Improvement in pain, in patients with spinal cord injury, can be seen as early as 1 week. To fully
evaluate the efficacy of the medication, it is recommended that administration continue for a period of 4–6 weeks, assuming tolerability of adverse reactions. Adverse events associated with the use of pregabalin are evident in the initial weeks of administration
and may dissipate with continued use. Among these events, the most common are dizziness, somnolence, dry mouth, fatigue, lower extremity edema and weight gain. Angioedema is a rare adverse reaction, but may occur during initial or chronic use of pregabalin and
requires emergency treatment and immediate discontinuation of drug. The treatment of neuropathic pain may not be effectively accomplished with a single medication or
even a combination of medications, and other nonpharmacological treatments may be helpful. If a combination of medications is used, pregabalin can be safely combined with tricyclic medications, other antiepileptic medications, NSAIDs and even opiates. The effect of combination therapies has not been thoroughly studied in neuropathic pain in spinal cord injury, but there should be caution if combining pregabalin with angiotensin-converting enzyme inhibitors as there is an increased risk of angioedema.
Department of Rehabilitation Medicine, University of Miami Miller School of Medicine, Miami, FL, USA Research Service, Department of Veterans Affairs Medical Center, Miami VA Healthcare System, Miami, FL, USA *Author for correspondence: [email protected] 1 2
10.2217/PMT.13.35 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(5), 359–367
part of
ISSN 1758-1869
359
REVIEW Dalal, Felix & Cardenas SUMMARY Pregabalin is the only US FDA-approved drug to date for neuropathic pain in spinal cord injured patients. Pregabalin is a novel GABA analog whose primary mechanism of action involves binding at the a2-d subunit of voltage-sensitive calcium channels. Efficacy is noted within the first several days of administration. Dosing is typically initiated at 150 mg/day in divided doses, but may be started at even lower doses. Dosing can be increased gradually to a recommended maximum of 600 mg per day in divided dosing. Adverse events include somnolence, dizziness and dry mouth, and typically manifest within the first 2 weeks of treatment. Pregabalin is generally safe to use in combination with other pain medications or antidepressants, but safety in pregnant patients has not been established. Background Pregabalin is used as a nonopioid analgesic for the treatment of a variety of conditions, most recently approved by the US FDA for the management of neuropathic pain associated with spinal cord injury. Neuropathic pain affects between 3 and 8% of the world’s population as a whole, and can impact various aspects of a patient’s functional abilities and quality of life [1]. Within the realm of spinal cord injury, neuropathic pain affects approximately 40% (100,000) of the 270,000 patients with spinal cord injury in the USA [1]. It emerges early in the postinjury period and may persist chronically for decades. Severe cases can significantly hinder the patient’s potential for rehabilitation and functional recovery. Neuropathic pain is thought to occur after sensory neuron damage, which leads to disorganized axonal sprouting and neuroma formation. These alterations in the nerve architecture consequently alter voltage-gated channel expression. Although the mechanism of action is not precisely known, it is believed that pregabalin is able to inhibit neuronal hyperactivity traveling along these pain pathways by selectively binding the Ca 2+ a2-d subunit in the CNS. This in turn reduces calcium flow through the channel, thus reducing neurotransmitter release from the presynaptic neuron. Hence, transmission is reduced, and nociceptive signaling is reduced [2]. Indications & usage
Pregabalin was recently approved, as of June 2012, by the FDA for the treatment of neuropathic pain associated with spinal cord injury [101]. To date, pregabalin is the only medication approved for this indication in spinal cord injury (SCI). So far, the FDA has approved five indications for treatment by pregabalin. Prior to its approval for neuropathic pain in SCI, other indications included: neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia and as adjunctive therapy for adult patients
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Pain Manage. (2013) 3(5)
with partial-onset seizures [102]. Pregabalin is a structural derivative of the inhibitory neuro transmitter GABA. However, it does not bind directly to GABA-A, GABA-B or benzodiazepine receptors, nor does it augment GABA-A response in cultured neurons. Furthermore, pregabalin does not augment GABA-A responses in cultured neurons, alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter proteins and increases the rate of functional GABA transport [102]. Initially, the FDA approved pregabalin for the treatment of pain associated with diabetic peripheral neuro pathy and postherpetic neuralgia, becoming the first medication approved in both Europe and the USA to treat both of these conditions [2]. Shortly thereafter, pregabalin was approved as an adjuvant medication in the treatment of partial-onset seizures [2]. Pregabalin’s structuraly related predecessor in the treatment of neuropathic pain is gabapentin. Gabapentin has also been shown to be effective in treating neuropathic pain in SCI and was originally designed as a GABA-mimetic agent that freely crosses the blood–brain barrier [3]. A review of multiple studies examining the use of gabapentin or pregabalin in the treatment of neuropathic pain in SCI suggested that pregabalin was more efficacious in several measures when compared with gabapentin, and both medications had a better tolerability and safety profile than either opioids or tricyclic antidepressants [3]. Despite being considered as antiepileptic medications, some emerging predominant indications for use besides neuropathic pain include fibromyalgia and generalized anxiety disorder. As of 2008, 40% of pregabalin sales were for the indication of neuropathic pain [4]. One common denominator between epilepsy and such nonepileptic disorders is altered neuronal excitability caused by abnormally functioning membrane
future science group
Pregabalin for the management of neuropathic pain in spinal cord injury ion channels [1]. However, the utility of antiepileptic drugs, such as pregabalin, in treating other neurologic and psychiatric disorders is due to a combination of factors; included among these are multiple mechanisms of action, diverse efficacy, low potential for interactions and favorable tolerability profile. In 2007, pregabalin became the first medication to be FDA approved for the treatment of fibromyalgia [5]. Despite a constellation of symptoms, pain associated with fibromyalgia is ranked by clinicians and patients as having the greatest impact on quality of life in this patient group [5]. Dosage & administration
Although there may be variations in different countries, in the USA, pregabalin is available as an oral solution containing 20 mg/ml, and as capsules in 25, 50, 75, 100, 150, 200, 225 and 300 mg. The recommended initial dosing for all indications is 150 mg/day, which may be increased based on efficacy and tolerability. Depending on the indication, pregabalin is given in divided doses, either two-times a day for fibromyalgia or neuropathic pain associated with SCI, or three-times daily for painful diabetic neuropathy. Pregabalin can be given two-times a day or three-times daily for postherpetic neuralgia, or as adjunctive therapy for adults with partial-onset seizures. For all indications, the dose may be increased to 300 mg/day within 1 week, based on efficacy and tolerability. For fibromyalgia, neuropathic pain associated with SCI and postherpetic neuralgia, pain relief may not be achieved until higher doses are reached. Studies show therapeutic results at dosing as high as 600 mg total per day for postherpetic neuralgia and neuropathic pain associated with SCI. Because pregabalin is eliminated primarily by renal excretion, the dose in patients with reduced renal function should be adjusted [102]. Some resources recommend a maximum dose of pregabalin at 100 mg three-times daily (300 mg/day) in patients with creatinine clearance of at least 60 ml/min. Supplemental dosing may be considered immediately following hemodialysis [6]. A review article discussing studies from 1993 to 2005 showed that there was not a significant difference between dosing at 75 mg/day versus placebo in patients with neuropathic pain due to various etiologies [6]. By the end of the first week, efficacy could be detected. Maximum efficacy was typically reached at a specific dose within the first week of its administration. Dosing between
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300 and 600 mg/day was shown to significantly reduce neuropathic pain in postherpetic neuralgia and diabetic neuropathy. Clinical pharmacology Mechanism of action
Pregabalin is a novel GABA analog whose primary mechanism of action involves binding at the a2-d subunit of voltage-sensitive calcium channels [7]. Binding decreases calcium influx through the calcium channels, leading to a reduction in the release of several neurotransmitters, including glutamate, substance P and noradrenaline [8]. Pregabalin, thus, has a modulating effect on the release of specific neurotransmitters that are implicated in neuropathic pain, partial seizures and anxiety [6]. Although pregablin is a chemical analog of GABA, the drug has no GABA-ergic activity. When compared with gabapentin, a drug with a similar mechanism of action, pregabalin is more potent than gabapentin and has a threefold greater rate of absorption [9]. In a recent study of persons with neuropathic pain and SCI using magnetic resonance spectroscopy, reduced metabolite concentrations in the anterior cingulate cortex of glutamate– glutamine/inositol ratios were found in those with severe neuropathic pain and a significant psychosocial impact [10]. In a recent randomized controlled crossover study of pregabalin versus placebo in persons with fibromyalgia, reduced concentrations of glutamate–glutamine/creatinine in the posterior insula were found, suggesting that these changes may be related to its mechanism of action [11]. Further research in humans is needed to determine whether pregabalin alters glutamate–glutamine and other brain metabolites in persons with SCI and neuropathic pain. Pharmacokinetics
Pregabalin is administered orally and readily absorbed into the blood stream reaching a peak concentration within 1 h [9]. Absorption occurs within the small intestine and the ascending portion of the colon [12]. The blood concentration in healthy subjects has a linear relationship over a dose range of 75–900 mg per day [13]. It has not been determined whether this linear relationship holds for persons who have a neurogenic bowel, such as spinal cord-injured patients. The bioavailability of pregabalin is high, averaging ≥90% in healthy subjects [14]. Agents that reduce small bowel motility are not expected to have a significant effect on the absorption of pregabalin.
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REVIEW Dalal, Felix & Cardenas Only the rate of absorption is affected by food so it can be taken with or without food [14]. After oral ingestion, pregabalin is found in the blood as well as in the cerebrospinal fluid, although the peak cerebrospinal fluid concentration occurs at 8 h in healthy subjects. The half-life of pregabalin is approximately 6 h. Pregabalin is not bound to plasma proteins nor does it inhibit CYP450 enzymes. Renal excretion is the primary pathway for elimination, necessitating dose adjustments for those with impaired renal function, as discussed previously [15]. Clinical evidence Overview of clinical trials
To evaluate the literature related to the treatment of neuropathic pain in persons with SCI, PubMed and CINAHL were searched using the terms ‘pregabalin’ or ‘Lyrica’ and ‘spinal cord injury’ ‘spinal cord injuries’, or ‘SCI’. These searches yielded a total of 27 publications: five articles of clinical trials or case studies related to the effectiveness and/or side effects of pregabalin for the treatment of neuropathic pain in persons with SCI; one case study related to pregabalin for treatment of prurigo in a patient with SCI; 11 review articles; six articles using rodent models of SCI; two articles measuring outcomes not related to pain; one clinical trial for a drug other than pregabalin; and one comment on a previously published article. Review of these articles revealed two published randomized, double-blind controlled studies that have specifically investigated the efficacy of pregabalin in adult subjects (≥18 years old) with below-level central neuropathic pain associated with SCI [16,17]. One additional clinical trial has reported on the efficacy of pregabalin in a sample of subjects with central neuropathic pain of different etiologies, with a majority (52.5%) of subjects having central neuropathic pain due to SCI [18]. Details regarding subject selection, methods and results for each of these studies are shown in Table 1. The two large studies performed exclusively in persons with SCI included data from 137 and 220 subjects, over a 12- and 16-week treatment period, respectively [16,17]. The Siddall et al. study was performed in eight sites in Australia [16], while the Cardenas et al. study included 60 sites in ten countries in North America, South America, Asia and Europe [17]. Similar inclusion criteria were used in both studies: tetraplegic and paraplegic patients, with either incomplete or complete SCIs, who had
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chronic neuropathic pain (continuously for the past 3 months or relapsing and remitting for the past 6 months) that was rated an average of at least 4 on a 0–10 numerical rating scale of pain intensity. Both studies also allowed patients to continue other stable analgesic regimens, with the exception of gabapentin or pregabalin. Those who were taking gabapentin or pregabalin were required to discontinue at least 1 week prior to study entry. All three studies that have included SCI patients with central neuropathic pain utilized a dose escalation protocol, with dosing starting at 150 mg/day and increasing to a maximum of 600 mg/day, dependent on efficacy and tolerability in each subject [16–18]. Average stabilized dose was reported as 460 mg/day in the Siddall et al. study [16], and 410 mg/day in the Cardenas et al. study [17]. All studies utilized intention-to-treat analyses, and reported patient flow through the trial, including details regarding subject discontinuation/drop-out. Results from these studies support the effectiveness of pregabalin for reducing central neuro pathic pain associated with SCI. Significant differences in daily pain ratings at the end of the treatment protocol were reported between subjects receiving pregabalin and those receiving an inactive placebo. The small study of mixedpathology (spinal cord and brain injury) central neuropathic pain also found a statistically significant decrease in pain intensity ratings during the final week of a 4-week pregabalin treatment trial [18]. In the Siddall et al. study, the end point mean pain score (average of daily ratings of pain intensity during the final week [week 12] of treatment controlled for baseline ratings of pain intensity) was significantly lower for the pregabalin group (numerical rating scale score = 4.62 ± 2.1; mean ± standard deviation) compared with the placebo group (6.27 ± 2.1) [16]. Similarly, the Cardenas et al. study reported significantly greater duration-adjusted average decrease in numerical pain ratings for the pregabalin group (-1.66 ± 0.16; least squares mean ± standard error) compared with the placebo group (-1.07 ± 0.15) when comparing the 16-week end point with baseline ratings of pain [17]. Both studies also reported that a reduction of pain ratings was apparent within the first week of treatment with pregabalin [16,17]. Using responder analyses, the number needed to treat (NNT), based on 30% pain reduction, was calculated at 3.9 in the Siddall et al. study [16]
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Pregabalin for the management of neuropathic pain in spinal cord injury and seven in the Cardenas et al. study [17], and both studies reported a NNT of seven for 50% pain reduction. Efficacy of pregabalin was also consistent across the two studies for secondary outcome measures, including significantly decreased sleep interference and significantly greater Patient Global Impression of Change ratings for subjects receiving pregabalin compared with those receiving placebo [16,17]. Although the NNT for patients with moderate-to-severe central neuropathic pain associated with SCI appears to be higher than the NNT (3.9) for patients experiencing peripheral neuropathic pain due to diabetic peripheral neuro pathy or postherpetic neuralgia [19], the two published studies in SCI provide class I evidence (blinded, randomized, controlled and adequately powered) for the effectiveness of pregabalin for this notoriously difficult to treat central pain condition [16,17], which resulted in FDA approval of pregabalin for the treatment of neuropathic pain in SCI. Titrated doses of between 300 and 600 mg/day were found to be appropriate for most subjects, and balancing of effective pain reduction with tolerable adverse events on a patient-by-patient basis was suggested. Other clinical evidence
In addition to clinical trial studies of pregabalin for the treatment of neuropathic pain in persons with SCI, a limited number of other publications support the potential efficacy of pregabalin in this patient population. In a sample of 72 patients in the UK who were prescribed pregabalin for pain associated with chronic SCI, measures of compliance and persistence with pregabalin therapy were high, suggesting good efficacy and tolerability for pregabalin in these patients [20]. However, estimates of total medical costs (including costs associated with outpatient, emergency room and hospital visits, and medication and procedure costs) during the 9-month period after initiating treatment with pregabalin were statistically significantly higher compared with the 9-month period preceding the initiation of pregabalin [20]. A case report by Westermann et al. detailed the effect of pregabalin in a patient with chronic SCI and neuropathic pain in the area at the neurological level of injury [21]. Although the patient reported the same symptoms and severity of clinical pain bilaterally, quantitative sensory testing and intraepidermal nerve fiber density testing revealed differences in fiber-density and nerve
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function between the left and right sides of the body in the area of neuropathic pain. Administration of 300 mg/day pregabalin reduced pain intensity on the side of the body with greater residual sensory function from 8 to 2 on a numerical rating scale, but did not reduce reported pain intensity on the other side. The authors suggest that, based on the sensory testing and fiber density results, differences in mechanisms related to neuropathic pain were revealed for different sides of the body in this patient, and that these differences in mechanism were related to the unilateral effectiveness of pregabalin at the dose utilized [21]. Future research should be aimed at investigating whether patients with specific phenotypes or identified mechanisms of neuropathic pain may be more likely to benefit from treatment with pregabalin than other patients. Safety & tolerability Adverse reactions
Pregabalin has been deemed to have a low potential for abuse relative to other drugs in schedule IV, and even in the case of abuse, it has a low potential for physical or psychological dependence relative to this same cohort. Therefore, pregabalin was placed in schedule V by the FDA [22]. Although a majority of SCI subjects taking pregabalin reported at least one adverse event during treatment trials (96 [16] and 67% [17]), a large proportion of subjects taking placebo also reported adverse events (75 [16] and 47% [17]). The severity of side effects was generally mild, with 5 and 21% of subjects in the pregabalin group and 5 and 13% of the placebo group, withdrawing due to adverse events from the Cardenas et al. [17] and Siddall et al. [16] studies, respectively. The most commonly reported side effects of pregabalin were somnolence, dizziness and peripheral edema (Table 1). In addition to these conditions, other adverse events reported by at least 10% of subjects randomized to pregabalin in the Siddall study included: asthenia/loss of strength, dry mouth, constipation and amnesia [16]. No clinically relevant changes in laboratory tests (hematology, chemistry and urina lysis), physical examination or EKG results were reported in either study. Reported incidence of somnolence in SCI subjects taking pregabalin appear to be higher than that reported in other patient populations. Approximately 15–25% of patients with postherpetic neuralgia, and 5–16% of those with diabetic peripheral neuropathy reported
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REVIEW Dalal, Felix & Cardenas Table 1. Randomized controlled trials of pregabalin in persons with neuropathic pain associated with spinal cord injury. Study (year)
Drug
Siddall et al. (2006)
Vranken et al. (2008)†
Subjects n
Design
Results
Average age (years)
Male (%)
Treatment Average dosage, weeks in mg/day (range) trial (n)
Mean difference Subjects with >30% Subjects with in pain rating pain relief (%) >50% pain relief from baseline to (%) end point
Placebo 67 Pregabalin 70
49.8 50.3
81 86
12
– 460 (150–600)
-0.46 -1.92
16 42
8 22
Placebo 20 Pregabalin 20
55 54
50 55
4
– Not reported (150–600)
-0.1 -2.5
10 35
5 35
85 76
16
– 410 (150–600)
-1.07 -1.66
31 46
15 30
Cardenas Placebo 107 45.6 et al. Pregabalin 112 46.1 (2013)
Included patients with central neuropathic pain of both brain and spinal cord etiology. A total of 50% of subjects in the placebo arm were spinal cord injury and 55% of subjects in the pregabalin arm were spinal cord injury. Results presented in this table are for all subjects (spinal cord and brain injury or disease). The authors reported that degree of pain relief during pregabalin treatment did not significantly differ between subjects with spinal cord injury and those with brain injury. EQ-5D: EuroQol instrument 5D; HADS: Hospital Anxiety and Depression Scale; MOS-SS: Medical Outcomes Study Sleep Scale; SF-MPQ: Short Form – McGill Pain Questionnaire; PGIC: Patient Global Impression of Change; VAS: Visual analog scale. †
somnolence during treatment with pregabalin [23–25], compared with between 33 and 41% of those with SCI-related neuropathic pain [16,17]. A comprehensive review including subjects treated with pregabalin for neuropathic pain, epilepsy and generalized anxiety disorder, reported that up to 50% of subjects identified somnolence as an adverse effect in the clinical trials included in the review [6]. It has been suggested that the greater percentage of subjects with SCI reporting somnolence may be due to additional pharma cologic agents taken by SCI subjects, particularly antispasticity/sedating medications that may have additive CNS effects with pregabalin to increase somnolence. The frequency of reports of dizziness in the SCI samples, however, are similar to those reported in other populations (18–24% [16,17] vs 13–35% in postherpatic neuralgia [23,24] and 23% in diabetic peripheral neuralgia [25]), as were reports of peripheral edema (10–12% [16,17] vs up to 16% in diabetic peripheral neuropathy [25] and 19% in diabetic peripheral neuropathy and posteherptic neuralgia studies combined [26]). Weight gain was reported as an adverse event in less than 5% of SCI subjects taking pregabalin [16,17]. However,
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measured weight gain in the pregabalin group was an average of +2.0 kg in the Siddall et al. study [16] and +0.8 kg in the Cardenas et al. study [17], compared with average weight losses of -0.8 kg [16] and -0.4 kg [17] in the placebo groups, and clinically significant weight gain (≥7% increase) was recorded in 11.4% of patients taking pregabalin over 12 weeks (compared with 3.1% of patients taking placebo) [16]. Across clinical trials of pregabalin for a variety of other patient groups, approximately 15% of subjects gain ≥7% of their baseline weight at or approximately 2 months after medication onset [26]. Other, less frequent, adverse outcomes reported are abnormal thinking, asthenia, infection, mouth dryness, diplopia, nervousness, amblyopia, amnesia, diarrhea and incoordination [6]. In summary, the most common adverse events related to pregabalin use for central neuropathic pain in SCI are somnolence, dizziness and peripheral edema. The severity of these events was generally reported as mild or moderate and adverse events led to study withdrawal in only approximately 5–20% of subjects. In addition to these common side effects, some caution should be used when prescribing pregabalin in persons with heart
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Pregabalin for the management of neuropathic pain in spinal cord injury
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Table 1. Randomized controlled trials of pregabalin in individuals with neuropathic pain associated with spinal cord injury (cont.). Results (cont.)
Subjects with adverse events (%)
Ref.
Primary outcome summary
Secondary outcome summary
>1 adverse event
Somnolence Dizziness Peripheral edema
Significantly (p
