Adjunct Medications for Pain Management

Gabapentin (Neurontin, Gralise, Horizant)

Gabapentin is a non-opioid medication that has been ubiquitously used for chronic pain management. The standard initial dose of gabapentin is dependent on the particular gabapentin formulation used. For the first available preparation of gabapentin (Neurontin), it is 100 to 300 mg daily. Although the United States Food and Drug Administration (FDA)-approved therapeutic dose of this preparation for the treatment of postherpetic neuralgia (PHN) (the only chronic pain condition for which this preparation is FDA-indicated) is 1800 mg, many clinicians will start with a lower dose with a gradual increase to a maximum of 3600 mg/day administered in three divided doses as tolerated ( Table 54.2 ). To minimize the consequence of certain adverse effects such as sedation and dizziness, the initial dose is often given at bedtime. After two to five days, the dose is increased to 300 mg twice daily and, after another two to five days, to 300 mg three times daily after that. Then the dose can be increased by 300 to 600 mg every few days as tolerated until an effective dosage is obtained, the maximum daily dose is reached, or side effects appear. A gastric-retentive formulation of gabapentin (Gralise) has also been approved by the FDA for PHN. It is intended to provide a simpler dosing paradigm than needed with the traditional generic gabapentin through the use of a polymer-based technology that allows gastric retention of the pill for extended delivery of the active medication. Another formulation of gabapentin, gabapentin enacarbil (Horizant), was developed and initially approved to treat restless legs syndrome. It is an actively transported prodrug form of gabapentin that allows twice-a-day dosing because of increased stability in bioavailability compared to the standard formulation of gabapentin. In a randomized controlled trial (RCT), this prodrug formulation was also found to be effective in the treatment of PHN when given twice per day. This drug is approved by the FDA to treat PHN and restless leg syndrome.

The primary dose-limiting side effects of gabapentin are fatigue, somnolence, and dizziness, which are often attenuated by gradual dose titration. Although gabapentin has few drug interactions, a reduced dosage is necessary for patients with renal insufficiency. However, starting dosages of gabapentin often do not provide immediate pain relief, and the slow titration requirements may result in adequate pain relief taking up to two months to achieve when given as immediate-release gabapentin. When given as the extended-release formulation, therapeutic doses can be reached in approximately two weeks.

Gabapentin has uses in multiple chronic pain conditions. Studies have been performed on patients being treated for PHN, complex regional pain syndrome (CRPS), painful diabetic neuropathy (PDN), and other forms of neuropathic pain (NP) and pain of controversial etiology, including fibromyalgia and opioid-induced hyperalgesia. A meta-analysis of 5914 participants in 37 studies found substantial benefits (at least 50% pain relief or “very much improved” on the patient global impression of change [PGIC] scale) for patients with PHN and PDN. Common side effects across the entire meta-analyzed population included dizziness (19%), gait disturbance (14%), somnolence (14%), and peripheral edema (7%). Among 2260 patients with PHN from eight studies, 32% of subjects had a substantial response to gabapentin ≥1200 mg daily compared with 17% of subjects receiving placebo (RR 1.8 [95% confidence interval [CI] 1.5 to 2.1]; number needed to treat (NNT) 6.7 [5.4 to 8.7]). When “moderate benefit” (at least 30% pain relief or PGIC of “much improved” or “very much improved”) was examined, 46% of PHN participants met these criteria compared with 25% of those taking placebo (RR 1.8 [95% CI 1.6 to 2.0]; NNT 4.8 [4.1 to 6.0]). Evidence for both of these outcomes was graded as moderate quality. The same meta-analysis found that among 1277 PDN patients across six studies, 38% receiving gabapentin ≥1200 mg/day derived substantial benefit compared with 21% of subjects receiving placebo (RR 1.9 [95% CI 1.5 to 2.3]; NNT 5.9 [4.6 to 8.3]). Similarly, 52% of subjects receiving gabapentin had moderate benefit, while 37% of those receiving placebo did (1439 total participants across seven studies; RR 1.4 [95% CI 1.3 to 1.6]; NNT 6.6 [4.9 to 9.9]). Evidence was again graded as moderate quality. Of note, very limited data are available for gabapentin use in other neuropathic pain conditions such as nerve injury, spinal cord injury, and radicular leg pain despite this medication being commonly used for these indications. Other meta-analyses have looked at gabapentin use in phantom limb pain, showing a mean Numerical Rating Scale (NRS) difference of –1.16 (95% CI –1.94 to –0.38) for gabapentin compared with placebo in a small total sample of 43 subjects, and in chronic low back pain (cLBP), unsurprisingly showing no significant improvement in pain compared with placebo in 185 subjects (mean NRS difference –0.22 [95% CI –0.5 to 0.07]), with low quality evidence. Overall, most guidelines for the treatment of NP include gabapentin as a first line agent.

Recent attention has focused on the potential for misuse and use disorder related to gabapentin, as well as the risk of morbidity and mortality when this medication is co-prescribed with opioids. A systematic review of 59 studies examining gabapentinoid misuse and abuse found a 1.6% prevalence of abuse among the general population but prevalence ranging from 3%-68% among opioid abusers; overall risk factors for abuse included a history of substance misuse, particularly opioids, and psychiatric comorbidities. Prescribers should exercise caution with gabapentin in these populations. A population-based nested case-control study of 1256 opioid users who died of opioid-related causes and 4619 opioid users found that opioid and gabapentin coadministration significantly increased the odds of opioid-related death compared with opioid use without gabapentin (adjusted odds ratio 1.49, 95% CI 1.18 to 1.88). The FDA recently added a black box warning to gabapentin (as well as pregabalin, discussed below), cautioning that respiratory depression and sedation may occur in elderly patients or those with respiratory conditions receiving gabapentinoids concurrently with central nervous system (CNS) depressants such as opioids and benzodiazepines.

Few studies have looked at the use of gabapentin on cLBP. One study by Atkinson et al. investigated gabapentin versus inert placebo for cLBP and found that within each treatment arm, there was statistically significant reductions in pain. However, when comparing gabapentin to placebo, there was no statistically significant difference in pain relief between the two groups.

Gabapentin has been reported as useful in the treatment of fibromyalgia. However, only one rigorous RCT has been published investigating gabapentin versus placebo for this condition. In this study by Arnold et al. 150 patients were randomized to either placebo or gabapentin (titrated to doses of 1200–2400 mg/day) for 12 weeks. Results showed that gabapentin-treated patients had significantly greater improvement in average pain scores of a modest effect.

Pregabalin (Lyrica)

Like gabapentin, pregabalin is used to treat chronic pain and acts by binding to the α ₂ δ subunit of L-type voltage-gated calcium channels, which results in decreased neuronal excitation. Pregabalin is approved by the FDA for the treatment of PHN, PDN, fibromyalgia, and spinal cord injury-associated pain. Initial pregabalin dosing is 150 mg/day given in two or three divided doses or 25 to 50 mg given at bedtime in elderly patients. Upward dose titration can be completed after three to seven days to 300 mg/day and subsequently increased to a maximum dose of 600 mg/day within two weeks of initiation. Similar to gabapentin, dosing of pregabalin must be decreased in patients with reduced kidney function. Advantages of pregabalin over gabapentin include a more rapid onset of pain relief, linear pharmacokinetics with low inter-subject variability, fewer dose-related side effects, thereby allowing faster upward dosage titrations, and twice daily versus three times a day dosing. Additionally, a maximum benefit often occurs after two weeks of treatment at target doses of 300 to 600 mg/day versus up to two months in gabapentin-treated patients. The advantage of pregabalin is its early response and favorable side effect profile. The most common adverse effects include somnolence and dizziness, and they occur more frequently with higher doses. When discontinuing pregabalin, it should be tapered down gradually over at least one week to minimize symptoms, including insomnia, nausea, headache, and diarrhea.

As with gabapentin, pregabalin’s efficacy has been established in patients with PHN and PDN. One meta-analysis included 11,906 patients from 45 studies. Among subjects with PHN, subjects taking pregabalin 300 mg daily were more likely to experience ≥50% pain relief (32% vs. 13%; RR 2.5 [95% CI 1.9 to 3.4]; NNT 5.3 [3.9 to 8.1] among 713 subjects across four studies) and ≥30% pain relief (50% vs. 25%; RR 2.1 [95% CI 1.6 to 2.6]; NNT 3.9 [3.0 to 5.6] among 589 subjects across three studies) compared with those taking placebo. A dose-response relationship was observed among this population: Subjects administered pregabalin 600 mg daily compared with those given placebo were more likely to attain ≥50% pain relief (41% vs. 15%; RR 2.7 [95% CI 2.0 to 3.5]; NNT 3.9 [3.1 to 5.5] among four studies with 732 participants) and ≥30% pain relief (62% vs. 24%; RR 2.5 [95% CI 2.0 to 3.2]; NNT 2.7 [2.2 to 3.7]) in three studies with 537 participants. Evidence for all PHN analyses was graded as moderate quality.

For PDN, subjects administered pregabalin 300 mg daily compared with placebo were more slightly more likely to obtain ≥50% pain reduction (31% vs. 24%; RR 1.3 [95% CI 1.2 to 1.5]; NNT 22 [12 to 200] among 2931 participants in 11 studies) and ≥30% pain reduction (47% vs. 42%; RR 1.1 [95% CI 1.01 to 1.2]; NNTB 22 [12 to 200] among eight studies with 2320 participants), and substantially more likely to report “much” or “very much” improved PGIC (51% vs. 30%; RR 1.8 [95% CI 1.5 to 2.0]; NNT 4.9 [3.8 to 6.9] in five studies with 1050 participants). As with PHN, more improvement was observed with the 600 mg daily dose than with 300 mg, with ≥50% pain reduction noted in 41% of those taking this dose compared with 28% of patients taking placebo (RR 1.4 [95% CI 1.2 to 1.7]; NNT 7.8 [5.4 to 14] in five studies with 1015 participants) and ≥30% pain reduction seen in 63% versus 52% on placebo (RR 1.2 [95% CI 1.04 to 1.4]; NNT 9.6 [5.5 to 41]; 611 participants from two studies). In the PDN studies, evidence for the 300 mg daily dose was graded as moderate quality, while evidence for the 600 mg dose was graded as low quality.

Benefit was also seen for pregabalin 600 mg daily dose in mixed or unclassified posttraumatic neuropathic pain: Meta-analysis of 1367 subjects from four studies showed ≥50% pain reduction in 34% of patients taking pregabalin compared with 20% of those taking placebo (RR 1.5 [1.2 to 1.9]; NNT 7.2 [5.4 to 11]; moderate quality evidence) and ≥30% pain reduction in 48% vs. 36% (RR 1.2 [1.1 to 1.4]; NNT 8.2 [5.7 to 15]; low quality evidence). Pregabalin was also more likely to be efficacious than placebo in central neuropathic pain. Among 562 participants in three studies, 26% (vs. 15%) obtained ≥50% pain relief (RR 1.7 [1.2 to 2.3]; NNT 9.8 [6.0 to 28]; low quality evidence) and 44% (vs. 28%) obtained ≥30% pain reduction (RR 1.6 [1.3 to 2.0]; NNT 5.9 [4.1 to 11]; also, low quality evidence). There was no evidence of benefit in HIV neuropathy when 674 subjects in two studies were meta-analyzed (moderate quality evidence) and limited data for other NP conditions, including cancer pain, polyneuropathy, back pain, and sciatica. Except for PHN, a daily pregabalin dose of 150 mg daily was found to be ineffective; clinicians should consider higher doses should therapy at lower doses prove unhelpful. Clinicians should also be cognizant of the potential for misuse, abuse, and respiratory depression with gabapentinoids, as discussed previously in this chapter.

Two studies have investigated pregabalin compared to active control groups, and pregabalin was not found to be superior to opioids or celecoxib for treatment of cLBP. However, celecoxib plus pregabalin was superior to monotherapy in the study by Romano et al.

Many studies have been performed investigating the use of pregabalin for the treatment of fibromyalgia syndrome. Seven RCTs have investigated pregabalin monotherapy at varying doses ranging from 150 to 600 mg/day and were found to have superior pain relief compared to placebo. Arnold et al. and Mease et al. both found that daily total doses of 300/450/600 mg were all superior in pain efficacy to placebo. Crofford et al. found that only 450 mg/day dosing was superior to placebo for pain efficacy (not 150 or 300 mg/day). At doses of 300 or 450 mg/day, Ohta et al. reported superior efficacy of pregabalin over placebo. Arnold et al. and Clair et al. also reported superior efficacy of pregabalin in pooled groups of pregabalin doses (300-450 mg/day) over placebo. Pauer et al. published that only a modest statistically significant effect over placebo was noted at 450 mg/day (not at 300 or 600 mg/day). In a study by Gilron et al. combination therapy of pregabalin plus duloxetine versus placebo or monotherapy was investigated, and the authors reported that combination therapy is superior to placebo and pregabalin monotherapy.

Zonisamide (Zonegran)

Zonisamide is indicated as adjunctive therapy for partial seizures in adults and became available in the United States in 2000. It acts by blocking T-type calcium channels and sodium channels; its action also increases the release of GABA. The initial dose is 100 mg/day for two weeks with increases of 200 mg/week to a target of 600 mg/day. There have been case reports on its usefulness for post-stroke pain and headache. A randomized, double-blind, placebo-controlled pilot study of the efficacy of zonisamide for the treatment of PDN revealed that pain scores on the visual analog scale (VAS) and Likert (psychometric response) scales decreased more in the zonisamide group than in the placebo group. However, these differences did not reach statistical significance. Side effects included ataxia, decreased appetite, rash, and renal calculi (resulting from the carbonic anhydrase inhibitor effect). Zonisamide is contraindicated in those with sulfonamide allergy because it is a sulfonamide derivative, and the drug is approximately 40% bound to plasma proteins. Children have an increased risk for oligohidrosis and susceptibility to hyperthermia. Convincing data for zonisamide’s efficacy in other chronic pain syndromes has yet to appear.

Ziconotide (Prialt)

Ziconotide is a ω-conopeptide (previously known as SNX-111) that is administered intrathecally because of its peptidic structure. It is derived from the venom of a marine snail (genus Conus ). Ziconotide blocks calcium influx into N-type calcium channels in the dorsal horn laminae of the spinal cord, thus preventing afferent conduction of nerve signals. The administration is via an intrathecal infusion pump, and dosing should be started low, at a recommended dose of 2.4 µg/day (0.1 µg/h). Because of a lag time, it should be titrated up slowly at intervals of no more than two to three times per week to a recommended maximum of 19.2 µg/day. Ziconotide does not cause tolerance, dependence, or respiratory depression, and adverse effects primarily involve the CNS and range from dizziness, ataxia, confusion, and headache to frank psychosis and suicidal ideation.

Ziconotide monotherapy’s effect on chronic NP has been meta-analyzed from three RCTs with a total of 586 subjects. The pooled OR of ≥30% pain reduction with ziconotide vs. placebo was 2.77 (95% CI 1.37 to 5.59). Serious adverse events were common in the included studies, but evidence shows that these may be decreased by slow titration. A prospective multicenter observational registry of ziconotide use (either as monotherapy or with other intrathecal medications) observed ≥30% pain reduction in 17.4% of patients at 12 weeks and 38.5% of patients at 18 months. Nearly all patients included in the registry experienced side effects, including 22.6% with confusion.

The role of ziconotide in the management of chronic pain has yet to be fully elucidated. Currently, ziconotide is approved for the management of severe chronic pain in patients in whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatments, including intrathecal opioids, local anesthetics, and α-adrenergic agonists. However, this medication should be used cautiously because of its poor side effect profile. Particular attention should be paid to patients with preexisting psychiatric disease.

Phenytoin (Dilantin)

Besides the widespread use of phenytoin for seizures, it was the first anti-convulsant to be used for NP, with a 1940s report on its use for TN. Phenytoin is known for its nonlinear metabolism, which is manifested as marked increases in plasma level with small increases in dose after saturation of metabolism. Around 95% of a phenytoin dose is excreted as metabolites from the cytochrome P-450 system. The initial dosage of phenytoin is 100 mg two to three times daily. It has primarily been used for the treatment of diabetic neuropathy. However, because of the mixed results of its efficacy and high side effects and medication interaction profile, it has fallen into disuse. Phenytoin provides pain relief by blocking sodium channels, thereby preventing the release of excitatory glutamate and inhibiting ectopic discharges.

Intravenous phenytoin has been studied in the chronic pain setting, but data are limited. A systematic review and meta-analysis did not identify any studies warranting inclusion. Side effects of phenytoin include slowing of mentation and somnolence, with nystagmus and ataxia occurring in some patients. Among the epileptic drugs, phenytoin is unique in the development of facial alterations, including gum hyperplasia and coarsening of facial features. Fosphenytoin, an intravenously administered prodrug that converts to phenytoin, is used by some to avoid long dosing intervals or initial burning at the injection site.

Phenytoin activates the cytochrome P-450 enzyme system in the liver, and hence careful assessment of co-therapy is warranted. For example, phenytoin decreases the efficacy of methadone, fentanyl, tramadol, mexiletine, lamotrigine, and carbamazepine. As a result, dosages of these medications should be adjusted accordingly. Coadministration with anti-depressants and valproic acid could lead to an increased blood concentration of phenytoin, thereby lowering the subsequent doses required for effect in patients. Most would not use phenytoin for the treatment of NP except perhaps in refractory situations.

Carbamazepine (Tegretol)

Carbamazepine has been used in the United States since the 1980s to treat partial and generalized tonic-clonic seizures. Interestingly, it was first approved by the FDA for the treatment of TN, not for epilepsy. Besides its anti-convulsant and TN indications, it is used frequently for bipolar disorder. It was one of the first anti-convulsants studied for the relief of NP. The analgesic properties of carbamazepine were first reported in 1962. It is chemically related to the TCAs; reports have included studies of its use for PHN, PDN, post-stroke pain, and pain in Guillain-Barré syndrome. The initial dosage of carbamazepine is 100 to 200 mg twice daily, titrated to effect, with typical dose ranges of 300 to 1200 mg/day administered in two divided doses. Common maintenance doses are 600 to 800 mg.

Common side effects include drowsiness, dizziness, nausea, and vomiting, which can often be limited by slow titration. Carbamazepine is associated with very deleterious side effects, including pancytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Carbamazepine is considered the pharmacologic treatment of choice for TN. Although the pathology of this severe neuropathic facial pain in one of the distributions of the trigeminal nerve has not been fully determined, the majority of cases are thought to be caused by compression of the trigeminal nerve at the pontine origin of the nerve by an aberrant loop of an artery or vein. Despite (and likely because of) its longstanding history of use for this condition, high quality evidence for the efficacy of carbamazepine in TN was found lacking in a recent meta-analysis. Only two small placebo-controlled studies of short duration from the 1960s were included, with an overall RR of 6.02 (95% CI 2.82 to 12.85). However, societal guidelines emphasize the excellent treatment response seen in four such small studies, with 58% to 100% of patients obtaining meaningful pain relief compared with 0% to 40% in placebo groups and an NNT <2. Regardless, TN is a disease process that in many patients is challenging to treat completely, with multiple agents often being required.

Carbamazepine has also been investigated for use in other chronic NP states, with a similar lack of high quality evidence. Combined meta-analysis of four studies including 188 patients with TN, PDN, and post-stroke pain calculated a RR of 6.5 (95% CI 3.4 to 12) with an NNT of 1.9 (95% CI 1.6 to 2.5) for ≥50% reduction in pain, with the caveat that studies were small and of short duration. Importantly, patients maintained on carbamazepine therapy should have blood tests done every two to four months because of increased risk for the development of agranulocytosis and aplastic anemia with this agent. Studies have noted that the number needed to harm (NNH) for severe adverse effects was 24 and for minor adverse effects, such as sedation, was three.

Oxcarbazepine (Trileptal)

Oxcarbazepine, the keto-analog of carbamazepine, was developed to preserve the membrane stabilizing effects of carbamazepine while minimizing minor adverse effects such as sedation and serious, life-threatening reactions. A major advantage of oxcarbazepine is that monitoring plasma drug levels and hematologic profiles is not generally necessary. Similar to carbamazepine, oxcarbazepine blocks sodium channels; it does not affect GABA receptors.

Significant hyponatremia (sodium <125 mmol/L) may develop during treatment with oxcarbazepine. This typically occurs during the first three months, with sodium levels normalizing within a few days of discontinuing the drug. Monitoring of sodium levels should be performed when instituting oxcarbazepine therapy. Frequently reported adverse effects of oxcarbazepine include dizziness, somnolence, nausea, and vomiting, which are generally well tolerated; dermatologic adverse effects such as Stevens-Johnson syndrome and toxic epidermal necrolysis have also been infrequently reported.

The superior side effect profile of oxcarbazepine over carbamazepine has led to its increased use. Published guidelines list it as “probably effective” for treating pain from TN based on two moderate quality RCTs showing equal efficacy of oxcarbazepine and carbamazepine in 130 patients, with 88% showing a reduction in pain attacks by 50%. Oxcarbazepine has also been found effective in treating TN in patients who had no positive response to carbamazepine, and physicians should consider substituting one for the other in patients with insufficient analgesic response. Meta-analysis of oxcarbazepine data has identified no appropriate placebo-controlled trials related to TN, and little evidence to support its use in other forms of NP such as PDN, radicular pain, and mixed neuropathy, although a single RCT of 146 patients with PDN did show a significantly greater number of subjects attaining ≥50% pain relief with oxcarbazepine compared with placebo (34.8% vs. 18.2%, RR 1.91 [95% CI 1.08 to 3.39], NNT 6 [95% CI 3 to 41]).