It is estimated that more than 100 million Americans spend each day in chronic pain, at a yearly cost of more than $600 billion in lost productivity and health care expenditures.1 A central theme outlined in a 2011 Institute of Medicine report was that despite the care of chronic pain patients being extremely costly, outcomes continue to remain relatively poor.1 Currently, physicians who treat patients in chronic pain are advised to provide comprehensive and multidisciplinary treatments. A multidisciplinary pain strategy typically includes physical therapies, psychological care, and pharmacologic management. Pharmacologic therapies are typically aimed at treating the underlying pathophysiologic mechanisms or are simply used for symptom-based treatment. Many practitioners rely on nonopioid medications to treat chronic pain; however, for some patients, opioid analgesics are utilized for the symptomatic treatment of chronic pain.
In 2016, in response to the increasing rates of opioid prescribing coupled with an epidemic of opioid use disorders in the United States, the Centers for Disease Control (CDC) published guidelines on the use of opioid analgesics for chronic nonmalignant pain.2 Opioid prescriptions increased per capita by 7.3% from 2007 to 2012, and in 2012 alone, 259 million prescriptions for opioid pain medications were written, enough for every adult in the United States to have a bottle of opioid medications.3,4 Evidence from the literature supports short-term efficacy of opioids for reducing pain and improving function in some pain conditions, but there is a paucity of evidence that suggests long-term benefits of opioids for chronic pain.5
The first recommendation of the CDC guidelines is that nonpharmacologic and nonopioid pharmacologic therapy is preferred for chronic pain and should be tried first.2 Nonopioid pharmacotherapy includes, but is not limited to, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), amine reuptake inhibitors (ARIs), and membrane stabilizers. The goals of this review are to provide the reader with data from prospective, randomized, controlled, and blinded clinical trials in which nonopioid medications were investigated for the treatment of chronic pain.
Studies eligible for this review had inclusion criteria of adults (≥18 years) with pain syndromes of chronic duration (≥3 months), including chronic low back pain (CLBP), myofascial pain syndrome (MPS), fibromyalgia (FM), postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), radicular pain (RP), and complex regional pain syndrome (CRPS) (Table 1). These conditions were chosen for this review because they represent the most common chronic pain syndromes that current pain management physicians treat. Studies must have investigated the efficacy of nonopioid medications (Table 1) compared to placebo or another medication using a prospective, randomized, controlled, and a blinded design (designated as PC-RCT). Studies were excluded unless the type of blinding used was explicitly stated in the prose of the article. Studies were included if their primary outcomes were the impact of the nonopioid pharmacotherapy on pain severity (including change in pain score from baseline, functional status, or proportion of patients with response).
To identify relevant articles, literature searches were conducted in Medline (PubMed), Cochrane Library, and Scopus, with no limitation on the year of publication. The database searches were performed from March 2017 to May 2017. An exhaustive search strategy including a base search term for the chronic pain condition coupled with a changing search term for the nonopioid medication investigated was employed. The search strategy and terms are provided in Supplemental Digital Content 1, Appendix 1, http://links.lww.com/AA/B956. Searches were limited to human species and the English language. Filters such as “clinical trial” or “randomized clinical trial” provided by the search engines were not used; the decision to designate as a PC-RCT was that of the authors after review of the study methodology. The reference sections of original studies, meta-analyses, systematic reviews, or evidence-based recommendations were manually screened independently by the authors for additional articles.
Study Selection and Data Abstraction
All authors independently screened each title and abstract for potential full-text review based on the aforementioned inclusion criteria. Disagreements were resolved through discussion and consensus. After the full-text of the studies was retrieved, each was again independently screened for eligibility by all authors, with disagreements resolved through consensus to arrive at the final set of included studies. Data extraction was carried out independently by all authors, using a standardized extraction form. Characteristics of the selected studies included methods, participants, intervention, and outcomes that were recorded on the standardized extraction form.
The literature searches revealed a total of 9566 citations, of which 7098 citations were excluded due to being unrelated or duplicates; 2468 citations were screened, and 2197 were excluded for the following reasons: review articles (narrative or systematic); meta-analyses; case reports/series; observational studies; retrospective studies; nonrandomized studies; nonblinded studies; acute pain population; nonpain efficacy primary outcome; publication a protocol for an upcoming trial; and studies that did not have a control arm (either placebo or active comparator). The final number of studies included that investigated the efficacy of nonopioid analgesics on chronic pain syndromes was 271 (Supplemental Digital Content 2, Figures 1–7, http://links.lww.com/AA/B957).
FINDINGS FROM STUDIES GROUPED BY CHRONIC PAIN SYNDROME
Chronic Low Back Pain
CLBP is one of the most commonly encountered conditions in clinical practice. Despite its prevalence, it is a condition that leads to high medical utilization and disability and, unfortunately, there are few effective interventions.6 Treatment of CLBP includes the use of prescription medications such as acetaminophen, NSAIDs, ARIs, membrane stabilizers, and other miscellaneous nonopioids or opioids. Despite the fact that CLBP is the second most common reason that symptomatically drives people to see their physicians, there are no on-label Food and Drug Administration (FDA)–approved medications for this condition. The treatment of CLBP includes the use of a variety of prescription medications that do not have FDA approval for CLBP (Table 2).
Only 2 randomized, active-comparator controlled, double-blind trials met criteria for inclusion into this review.7,8 In the study by Bedaiwi et al,7 50 patients with CLBP were randomized to either acetaminophen (500 mg twice daily) or celecoxib (200 mg twice daily) for 4 weeks.7 After treatment, patients randomized to celecoxib had a 2-point reduction in their pain scores compared to a 0.5-point reduction in the acetaminophen group. Hickey8 enrolled a total of 30 patients into a study comparing diflunisal (500 mg twice daily) with acetaminophen (1000 mg 4 times daily) and found that diflunisal was superior in reducing pain scores compared to acetaminophen.
Nonsteroidal Anti-inflammatory Drugs.
Seven studies investigating oral NSAIDs for the treatment of CLBP met inclusion criteria.9–15 Five studies found NSAIDs to be superior to placebo for CLBP for naproxen,9 etoricoxib,10,13 valdecoxib,11 and rofecoxib.12 In the study by Berry et al,9 diflunisal was not found to be superior to placebo for CLBP. Two studies investigated the effect of an NSAID compared to an active NSAID comparator on pain relief—both of these studies demonstrated efficacy of the study drugs, as well as noninferiority of either celecoxib compared to diclofenac15 or piroxicam compared to indomethacin.14
Amine Reuptake Inhibitors.
There were a total of 13 studies evaluating the efficacy of antidepressants for CLBP. These included 5 studies on tricyclic antidepressants (TCAs) and 8 studies on selective norepinephrine or serotonin reuptake inhibitors (SNRIs and SSRIs). Ward et al16 and Ward17 investigated comparative effectiveness of doxepin to desipramine in 2 separate studies and found that both doxepin and desipramine are effective in the treatment of CLBP, and in 1 of the studies, they found doxepin to be superior.16 Atkinson et al18 found that nortriptyline was superior to placebo for pain relief, and that low-dose desipramine provided superior relief of pain compared to placebo, high-dose desipramine, and fluoxetine comparison groups.19 Imipramine was not found to be statistically superior to placebo in the treatment of CLBP in a study of 60 patients.20 Duloxetine, an SNRI, has been studied in 5 RCT studies for the treatment of CLBP and was found to be superior to placebo in 4 of 5 of them at the end point of the study.21–24 The one negative study had statistically significant improvements in pain ratings at all time points except at the final assessment.25 Maprotiline, an SNRI, was found to be superior to paroxetine and active placebo (diphenhydramine) in 103 patients with CLBP at 8 weeks.26 SSRIs paroxetine and bupropion have not been shown to be superior to placebo for treatment of CLBP.27,28
Few studies have looked at the use of the anticonvulsant drug class on CLBP. One study by Atkinson et al29 investigated gabapentin versus inert placebo for CLBP and found that within each treatment arm, there was statistically significant reduction in pain, but when comparing gabapentin to placebo, there was no statistically significant difference in pain relief between the 2 groups. Two studies have investigated pregabalin compared to active control groups, and pregabalin was not found to be superior to opioids30 or celecoxib31 for treatment of CLBP; however, celecoxib plus pregabalin was superior to monotherapy in the study by Romanò et al.31 Muehlbacher et al32 studied the effects of topiramate on CLBP compared to inert placebo and showed that topiramate was superior to placebo in reducing pain scores.
The majority of randomized controlled trials evaluating the use of muscle relaxants for CLBP were studied in an acute pain setting instead of a chronic pain population, and after exhaustive searching, only 3 studies met the inclusion criteria. In a study by Baratta,33 105 patients with CLBP were randomized to carisoprodol, propoxyphene, or placebo for 14 days, and results showed that carisoprodol was significantly better than placebo in relief of pain, but there was no statistical difference between the improvement seen with carisoprodol versus propoxyphene. In a study by Brown and Womble,34 49 patients with chronic spine pain were randomized to cyclobenzaprine, diazepam, or placebo for 2 weeks. Results showed that patients receiving cyclobenzaprine or diazepam had superior pain relief compared to placebo group; however, there was no difference in the pain response between the cyclobenzaprine and the diazepam groups. Additionally, Basmajian35 reported no difference in short-term reduction of pain and muscle spasms in CLBP patients between cyclobenzaprine and placebo after 18 days.
Although tramadol and tapentadol have some activity at the μ-opioid receptor, they also work via norepinephrine and serotonin reuptake inhibition, and thus are included in this review. A total of 12 studies met inclusion criteria. Six studies found that tramadol, tramadol/acetaminophen, or tapentadol had superior efficacy for the treatment of CLBP compared to placebo.36–41 Schiphorst Preuper et al42 found that tramadol/acetaminophen was not superior to placebo for CLBP. In a study comparing celecoxib to tramadol, O’Donnell et al43 published that 200 mg celecoxib twice a day was superior to 50 mg tramadol 4 times a day in the relief of CLBP. Four studies comparing tramadol, tramadol/acetaminophen, or tapentadol to an active comparator showed superiority in pain relief over the control group (oxycodone,44 study drug plus pregabalin,45 codeine/acetaminophen,46 and NSAIDs47).
Topical Lidocaine Patch.
A study by Hashmi et al48 randomized 30 patients to either a 5% lidocaine patch or a placebo patch. After 2 weeks of use, both lidocaine and placebo patch groups reported a greater than 50% decrease in pain, suggesting that there may be no independent efficacy of 5% lidocaine patch for CLBP, but there is also a large and significant placebo effect, and that 5% lidocaine patch is not statistically significantly superior to placebo.
One study met inclusion criteria and found that capsaicin cream was superior based on pain relief (at least a 30% reduction in numerical pain score rating) to placebo cream in 154 patients over 3 weeks.49
Botulinum Toxin Type A.
A study by Foster et al50 involving 31 patients with CLBP being treated with botulinum toxin type A (BoNT-A) met criteria for inclusion. In this study, 15 patients received 200 units BoNT-A in the lumbar spine paraspinal muscles and 16 received normal saline injection. Those who received BoNT-A injections had superior pain relief compared to saline injections at 3 and 8 weeks after treatment.
In a study by Kleinböhl et al,51 it was found that in patients who received 100 mg amantadine, an N-methyl-d-aspartate (NMDA) antagonist compared to placebo over 1 week had no difference in pain rating scores at the end of the treatment period.
Tanezumab, a monoclonal antibody against nerve growth factor, is given intravenously and has been investigated in 2 different studies. Both studies evaluated the efficacy of tanezumab against naproxen and placebo. Both studies reported that tanezumab was superior to naproxen and placebo at both a 6-week pain outcome end point52 and a 16-week pain outcome end point.53
Myofascial Pain Syndrome
MPS is a common painful condition encountered in the general population. It is a localized muscle condition that presents with skeletal muscle pain and stiffness.54 Classically, it is defined by the presence of trigger points in specific musculature. The exact pathophysiology and etiology of myofascial trigger points and MPS is still unknown. Despite MPS being quite common, they are most often underdiagnosed or misdiagnosed conditions. The treatment of MPS includes the use of prescription medications; however, no medications are specifically FDA-approved for MPS, although many muscle relaxants have indications for muscle spasm. The treatment of MPS includes the use of a variety of prescription medications that do not have FDA approval for MPS (Table 3).
Nonsteroidal Anti-inflammatory Drugs.
Two studies were identified using injected or topical NSAIDs that met inclusion criteria. Frost55 investigated the efficacy of diclofenac trigger point injections versus lidocaine injections for chronic localized myofascial pain. This study found that in the short-term (5-hour follow-up period), diclofenac injections produced a significant improvement in pain score compared to lidocaine at 4 hours. Hsieh et al56 found that diclofenac sodium patch (60 mg) provided significantly superior pain relief compared to control patch after 8 days in patients with chronic myofascial pain of the upper trapezius muscle. No studies evaluating oral NSAIDs for chronic myofascial pain met criteria for inclusion.
Amine Reuptake Inhibitors.
One study met inclusion criteria and studied the efficacy of fluoxetine versus amitriptyline for musculoskeletal pain. Schreiber et al57 randomized 40 patients to either amitriptyline (50–75 mg/d) or fluoxetine (20 mg/d) for 6 weeks. The degree of pain relief within each treatment group was moderate to good at the end of the study; however, the difference in responses between drugs was not statistically significant.
The majority of published studies evaluating the use of muscle relaxants for MPS were either studied in an acute pain setting instead of a chronic pain population or did not meet other inclusion criteria, and after exhaustive searching, only 1 study met the inclusion criteria. In a study by Valtonen,58 118 patients were either placed on 1500 mg methocarbamol 4 times a day or placebo for 1 week. After 1 week of treatment, there was a statistically significant superiority of patients having effective pain relief compared to placebo.
Topical Lidocaine Patch.
A study by Affaitati et al59 was included in this review and compared the effects of a topical lidocaine patch (total daily dose 350 mg), placebo patch, and injection of 0.5% bupivacaine over one painful trigger point for a total of 4 days. This study found that lidocaine patches and local anesthetic infiltration were effective for pain and superior to placebo in the short-term for patients with MPS. Another study by Lin et al60 reported that 5% lidocaine patch used for 14 days in cervical MPS may be superior to placebo, but the significant difference between the 2 groups may have been skewed by an unexpected increase in pain in the placebo patch group.
Two studies were found to meet inclusion criteria investigating capsaicin patch for MPS: one compared efficacy to placebo patch,61 and the other compared to NSAID patch, NSAID patch plus transcutaneous electric nerve stimulation, and placebo.62 Neither study found that capsaicin patch provided superior pain control when analyzed to the comparator group.
Botulinum Toxin Type A.
The majority of available studies that met criteria for inclusion for MPS are in the study of BoNT-A for pain. All but one of the included studies investigated patients with cervical and shoulder girdle MPS and the majority utilized a placebo or control procedure. The sole study looking at lumbar MPS was performed by De Andrés et al63 and found that BoNT-A was not superior in efficacy to placebo but was efficacious in a within-group analysis. There were 7 studies that showed superior efficacy of BoNT-A injections for cervical MPS compared to saline,64–68 local anesthetic and dry needling,69 or steroid.70 Eight published studies had negative findings in which BoNT-A was not found to have superior efficacy to control procedure: either saline71–77 or local anesthetic.78 The discrepancies between positive and negative studies have been postulated to exist due to heterogeneous research design methodology and use of control procedures that are thought to produce analgesic benefits of their own.54
FM is the second most common “rheumatologic” disorder, second only to osteoarthritis.79 Depending on the diagnostic criteria used, the prevalence is from 2% to 8% of the general population.79 Pain in FM is often widespread and can be challenging and difficult to control. The treatment of FM includes the use of a variety of prescription medications that have FDA approval for FM and those that do not (Table 4).
Nonsteroidal Anti-inflammatory Drugs.
Two studies met inclusion criteria for this review. In the study by Yunus et al,80 46 patients with FM were randomized to either 600 mg ibuprofen 4 times a day or matched placebo for a total of 3 weeks. At the end of 3 weeks, pain rating scores between the 2 groups did not show superior efficacy for the ibuprofen group compared to the placebo group nor were there any within-group significant reductions in pain. Russell et al81 performed a 4-arm study investigating ibuprofen + alprazolam, ibuprofen + placebo, alprazolam + placebo, and placebo + placebo in 78 patients for 8 weeks. Their findings indicated that the ibuprofen + alprazolam group had significantly greater reduction than placebo + placebo group. Monotherapy groups appeared to have similar reductions in pain to the combination group, but no statistical analyses were performed.
Amine Reuptake Inhibitors.
A total of 29 studies were found to meet inclusion criteria and included studies on TCAs, SNRIs, and SSRIs. Milnacipran is an SNRI that is approved by the FDA for the treatment of FM, and 10 studies met criteria for inclusion in this review. Only one of these studies by Staud et al82 had a negative finding between milnacipran and placebo groups; however, statistically significant reductions of small magnitude were noted within groups. Nine studies, many with large sample sizes, showed superior efficacy in pain reduction with milnacipran compared to placebo.83–91 Twelve studies evaluated duloxetine, an SNRI that is approved by the FDA for treatment of FM. Nine of these studies demonstrated superior efficacy of duloxetine compared to placebo at varying dosages of the drug, with 60 to 120 mg being the most commonly studied.92–100 Three studies reported nonsuperior efficacy of duloxetine to placebo: 1 studied a 30-mg dose101,102; 1 studied a 60-mg dose; and 1 studied either a 60- or 120-mg dose.103
Six studies investigated the efficacy of TCAs for the relief of pain in FM. Four studies showed efficacy of the TCA amitriptyline that was superior to placebo.104–107 Heymann et al108 investigated amitriptyline and nortriptyline compared to placebo, and although there was reduction in pain noted with both TCAs, it was not statistically significantly different than placebo. In the study by Carette et al,109 amitriptyline was not superior to placebo but had significant within-group reduction in pain scores.
Very few RCT studies have investigated the impact of SSRIs on pain in FM. Fluoxetine, an SSRI, was investigated in a study by Goldenberg et al105 and was found to be superior to placebo when used in monotherapy or combined with amitriptyline. Controlled-release paroxetine has been investigated in a study by Patkar et al,110 whose findings indicate that it is superior to placebo for pain relief after 12 weeks of treatment in 116 patients.
A total of 8 studies have been reported for pregabalin that met criteria for this review. Seven of these studies investigated pregabalin monotherapy at varying doses ranging from 150 to 600 mg/d and were found to have superior pain relief compared to placebo. Arnold et al111 and Mease et al112 both found that daily total doses of 300/450/600 mg were all superior in pain efficacy to placebo. Crofford et al113 found that only 450 mg/d dosing was superior to placebo for pain efficacy (not at 150 or 300 mg/d). At doses of 300 or 450 mg/d, Ohta et al114 reported superior efficacy of pregabalin over placebo. Arnold et al115 and Clair and Emir116 also reported superior efficacy of pregabalin in pooled groups of pregabalin doses (300–450 mg/d) over placebo. Pauer et al117 published that only a modest statistically significant effect over placebo was noted at 450 mg/d (not at 300 or 600 mg/d). In a study by Gilron et al,118 combination therapy of pregabalin + duloxetine versus placebo or monotherapy was investigated, and the authors reported that combination therapy is superior to placebo and pregabalin monotherapy.
Only one RCT investigating gabapentin was identified that met inclusion criteria. In this study by Arnold et al,119 150 patients were randomized to either placebo or gabapentin (titrated to doses of 1200–2400 mg/d) for 12 weeks. Results showed that gabapentin-treated patients had significantly greater improvement in average pain scores of a modest effect.
Three studies regarding the use of cyclobenzaprine in the treatment of FM pain met inclusion criteria. Two of these showed superior efficacy for relief of pain over placebo120,121; however, in the Quimby et al120 study, the authors noted a significant bias in blinding in that due to side effects of the drug, they knew that they were getting the study drug and not placebo. Reynolds et al122 published a report showing that cyclobenzaprine was not superior to placebo in the treatment of FM pain.
In a study by Vaerøy et al,123 a combination analgesic containing carisoprodol/caffeine/acetaminophen was compared to placebo for pain in FM in 58 female patients with FM over 8 weeks. No between-group comparisons are reported in the article; however, there were statistically significant improvements within both treatment groups.
Only one study met our strict inclusion criteria by Bennett et al.124 In this study, the efficacy of tramadol/acetaminophen (up to a total dose of 300 mg tramadol/2600 mg acetaminophen per day) was compared with placebo in a total of 315 patients enrolled in the study, which lasted approximately 3 months. The authors reported that tramadol/acetaminophen significantly reduced pain severity compared to placebo at study end.
In a study by Noppers et al,125 24 FM patients were randomized to either a 30-minute infusion of ketamine (total dose 0.5 mg/kg) or active comparator midazolam (total dose 5 mg). The authors reported no significant differences in pain scores between treatment groups at either a 2.5-hour or 8-week follow-up time point; however, statistically significant differences were noted for within-group analyses for both treatments.
Olivan-Blázquez et al126 performed a study in 63 FM patients and randomized to either memantine, an NMDA receptor antagonist, at the dose of 20 mg daily for 6 months, or placebo. Compared to placebo, memantine significantly reduced pain score ratings at the end of the study period.
In the sole study that met inclusion criteria, Younger et al127 performed a randomized crossover placebo-controlled study in which 31 women with FM were placed on either oral low-dose naltrexone (4.5 mg/d) or placebo and followed for 16 weeks. At the end of the study, there was a significantly greater reduction in pain in the low-dose naltrexone group compared to those taking placebo.
Three studies met inclusion criteria and found that infusions of 240 mg of intravenous (IV) lidocaine once a week for 4 weeks, in patients with FM all taking amitriptyline, did not provide superior efficacy for pain relief compared to patients receiving placebo infusions.128–130
In a study by Clark et al,131 20 patients were randomized into a double-blind, crossover study investigating the efficacy of prednisone versus placebo for FM pain; each treatment was studied for 14 days. There was no improvement seen in patients taking prednisone versus placebo and, in fact, pain worsened with prednisone treatment over time.
Skrabek et al132 performed the one study on a cannabinoid for FM pain that met inclusion criteria. In this study, 40 patients were randomized to receive oral nabilone, a cannabinoid-1 receptor agonist, versus oral placebo. Findings from this study show statistically significant reductions in pain score at 4 weeks in patients taking nabilone versus placebo.
PHN develops after the reactivation of the herpes zoster virus (HZ) from its latent state. The incidence of HZ reactivation in the United States is around 500,000 cases per year, or approximately 2 cases per 1000 persons. Patients older than 70 years with HZ have a 50% risk of developing PHN, whereas patients younger than 40 years rarely develop it.133 The treatment of PHN includes the use of prescription medications that have FDA approval for PHN management and those that do not (Table 5).
Pregabalin was found to reduce “worst possible” pain intensity within 2 days of treatment inception and remained significant throughout two 8-week multicenter PC-RCTs134,135 and other trials.136,137 It also reduced sleep interference,134,135,137 improved general health satisfaction,134 health-related quality of life,135,136 and mood,135–137 and was associated with a significant impression of improvement assessed by the patient134–137 and clinician.134,135 Fifty percent of patients with baseline pain intensity had >50% relief compared to 20% in the placebo group over the study period RCT, yielding a number needed to treat (NNT) of 3.4134; similar percentages were observed in a subsequent PC-RCT, yielding an NNT of 3.6.138 The pain reduction occurs within 1.5–3.5 days.136 The minimal effective dose ranged from 150 to 200 mg/d,134–136 and the effect is dose dependent to 600 mg.134–136,138
Gabapentin has been shown to be effective in the reduction of pain intensity,139,140 improvement in sleep interference,139,140 quality of life,139,140 and mood,139,140 and patient-139 and clinician-139 reported improvement in pain in PC-RCTs. The pain reduction occurs within 1140 or 2139 weeks, and the NNT was 3.2.139 Similar results have been recorded in PC-RCTs in Canada141,142; however, these trials combined multiple neuropathic pain conditions including PHN. The minimal effective dose was 1800 mg/d.140 The gabapentin prodrug (gabapentin enacarbil, Pd-G) had a significant reduction in averaged 24-hour pain scores compared with placebo.143 The minimum effective dosage was 1200 mg/d. Single daily administration of gastroretentive gabapentin (Gr-G) was more effective than placebo in one study,144 but the same study found no difference when given twice daily.145 The data are further challenged, as a third trial found no benefit from single daily dose Gr-G but did find benefit from twice-daily dosing.146
The efficacy of oxcarbazepine has been examined in neuropathic pain conditions; however, the sample size of the PHN subgroup was insufficient to make conclusions.147 The efficacy of levetiracetam has been examined in a small RCT with encouraging results, but the pilot study has never been replicated in a larger population.148
Amine Reuptake Inhibitors.
The TCAs nortriptyline,149 desipramine,150,151 and amitriptyline151,152 have been shown to be effective in the reduction of pain intensity and improvement in sleep interference152 in PC-RCTs. There appear to be few differences between different TCAs in treatment efficacy.149 The pain reduction occurs within 2 weeks.150 Similar positive results have been recorded in PC-RCTs in Canada142; however, this nortriptyline trial combined neuropathic pain conditions including PDN. Pain relief was independent of depression, and there was no effect on mood by either amitriptyline152 or nortriptyline.149 The minimal effective dose ranged from 75 to 150 mg/d.152 Topical amitriptyline (2%) had no benefit compared to placebo.153,154
In a single PC-RCT, fluoxetine155 reduced the pain intensity of PHN but was less effective than desipramine. The minimal effective dose ranged from 20 to 60 mg/d.
PC-RCTs for PHN were identified for high-dose (8%) topical capsaicin. It provided significantly greater pain relief and was more long-lasting (12 weeks) than control (low-dose capsaicin, 0.04%), but this difference was modest in one study156 and not different in another.157 In subsequent trials, high-concentration capsaicin was significantly more beneficial than the low-dose control,158,159 and the first time period of significance was 2 weeks after therapy.159 Low-dose (<0.075%) topical capsaicin has been shown to be effective in the reduction of pain intensity, improved quality of life, and the patient’s impression of relief.160 The pain reduction occurs within 4 weeks after 4 times daily application.160
The lidocaine patch (5%) has been shown to be effective in the reduction of pain intensity161–164 in PC-RCTs.
Dextromethorphan has been shown to be ineffective in the reduction of pain intensity.165,166 Memantine was similarly found to be ineffective.165 Topical ketamine was ineffective in the treatment of PHN.153 Magnesium was found to be effective in reducing PHN pain, but the effect was only sustained during the IV infusion.167
Tramadol has been shown to be effective in the reduction of pain intensity and improvement in quality of life,168,169 sleep,169 and social and physical function.169 Relief onset was within 14 days.168 The average analgesic dose was 50–200 mg/d.169
Nonsteroidal Anti-inflammatory Drugs.
Cyclo-oxygenase-2 inhibitors were ineffective in the treatment of PHN-related pain.170 A single small trial found that topical diclofenac (1.5%) was effective in relieving neuropathic pain from CRPS and PHN; unfortunately, the number of PHN patients (n = 3) is insufficient to make any condition-specific conclusion.171 Ibuprofen had no benefit in a single trial.172
Intradermal injection of BoNT-A to painful skin has been shown to be effective in the reduction of pain intensity,173,174 improvement in sleep interference,173,174 and reduction in opioid use173 for up to 12–16 weeks.173,174 The pain reduction occurs within 1 week.173,174 Lorazepam had no benefit compared to placebo.175
The combination 2 effective medications such as nortriptyline/gabapentin142 and morphine/gabapentin141 has been shown to be more effective than either medication alone in the reduction of pain intensity, improvement in sleep interference, quality of life, and mood with reduction in common side effects. The lower side effects were attributable to lower dosages of the individual medications needed to achieve the same or greater pain reduction.
Painful Diabetic Neuropathy
The World Health Organization estimates that 150 million people had diabetes in the year 2000 and project 366 million by the year 2030.176 The prevalence of peripheral neuropathy in patients with diabetes was 43% and higher in type 2 (51%) than in type 1 (26%).177 The treatment of PDN includes the use of prescription medications that have FDA approval for PDN management and those that do not (Table 6).
Pregabalin (300 mg/d) has been shown to reduce “worst possible” pain intensity by 1.5 points (numerical rating scale) and 1.6 (visual analog scale) 1 week after treatment inception, which remained significant during the course of an 8-week multicenter PC-RCT.178 Furthermore, it improved mood, reduced sleep interference, and was associated with a significant impression of improvement assessed by the patient and clinician. In a separate trial, 52% of patients with baseline pain intensity in the high moderate to severe range had >50% relief compared to 24% in the placebo group over a 12-week RCT, yielding an NNT of 3.6.138 Similar positive results have been seen in PC-RCTs in China, Canada, Japan, Europe, and Korea.137,179–182 Subsequent RCTs found no improvement in pain intensity when using 150 mg/d183 and 300 mg/d,184,185 but curiously patients in the lower dose groups had a significant impression of improvement in their global well-being as compared to placebo.183 Earlier comparative studies showed that 300 mg was similarly effective to 600 mg.186
Gabapentin has been shown to be effective in the reduction of pain intensity141,142,187 and improvements in mood,187 sleep,142,187 quality of life,141,142,187 patient and clinician187 reported improvement in pain, and hemodialysis-associated pruritus188 in PC-RCTs. The pain reduction was found to occur within 4 weeks.142,187 Similar results have been recorded in PC-RCTs performed in Canada141,142; however, these trials included various types of neuropathic pain conditions including PDN. The minimal effective dose ranged from 1800 to 2400 mg/d.141,142,189,190 The Gr-G formulation of gabapentin,191 but not the gabapentin prodrug (gabapentin enacarbil, Pd-G),184 has shown similar efficacy and both show similar side-effect profiles to the original formulation of gabapentin. Of note, pregabalin was included as a positive control in the enacarbil study and its results on pain intensity did not replicate earlier studies.184
Topiramate has been shown to be borderline effective in the reduction of pain intensity, improvement in sleep interference, quality of life, and mood192 in 2 PC-RCTs,192,193 but ineffective in all domains in 2 others.193 In the positive trials, the pain reduction occurs within 8 weeks.192 The most consistent finding in all trials was weight loss. Significantly more subjects lost weight in the topiramate group than placebo control subject.192 In the positive trials, the minimal effective dose ranged from 100 mg/d.192,193
Lamotrigine has been shown to be minimally effective in the reduction of pain intensity in 2 PC-RCTs194,195 and no change in one.195 Subjects had no improvement in sleep interference, quality of life, patient-reported improvement in pain, or mood and the most common side effect was rash.194,195 In the positive trials, the minimal effective dose ranged from 400 mg/d, and pain reduction occurs within 6 weeks.
Oxcarbazepine has been shown to be borderline effective in the reduction of pain intensity196 in a single PC-RCT, but no different in 2 PC-RCTs.197,198 The pain reduction occurs within 2 weeks.196 The minimal effective dose in the single positive study was 1800 mg/d.196
In a small PC-RCT, zonisamide statistically improved pain intensity over placebo; however, this did not meet the authors’ preprescribed criteria for significant reduction of 2 points in pain intensity score.199
Amine Reuptake Inhibitors.
Duloxetine has been shown to be effective in the reduction of pain intensity,200,201 the improvement in sleep interference due to pain,200,201 in quality of life,200,201 and patient-200 and clinician-200 reported improvement in pain and mood200 in PC-RCTs. The pain reduction occurs within 1 week.200,201 Similar results have been shown in multicenter PC-RCTs,202–204 but a single Chinese PC-RCT did not replicate the pain relief.205 Pain relief was found to be dose dependent, and the minimal effective dose was 60 mg/d.200,202 No difference was noted between 60 mg and 120 mg/d.201 Longer-term studies showed maintenance of pain relief to 6 months206 and 1 year.207
Venlafaxine has been shown to be effective in the reduction of pain intensity and patient- and clinician-reported improvement in pain in PC-RCTs.208 The pain reduction occurs within 2209 or 6208 weeks, and the NNT was 4.5.208 Similar efficacy results have been reported in other small PC-RCTs.209 The minimal effective dose ranged from 150 to 225 mg/d.208
The TCAs desipramine,210,211 imipramine,212 and amitriptyline210,213–215 have demonstrated effectiveness in the reduction of pain intensity and improvement in sleep interference212,214,215 in PC-RCTs. No PC-RCTs were identified for nortriptyline. The pain reduction occurs within 3–5 weeks.210–213 Pain returned within 2 weeks of TCA discontinuation.211 Pain relief was independent of depression, and there was no effect on mood by either amitriptyline or desipramine210,213 except in a single desipramine trial.211 The minimal effective dose ranged from 90 to 150 mg/d,212,213 and the effects of amitriptyline were dose dependent to 150 mg/d.213
Paroxetine,216 but not fluoxetine,210 reduces the pain intensity of DPN, improves sleep interference, and improves nighttime pain. The pain reduction occurs within 1–5 days.216 Similar efficacy results have been reported in another small PC-RCT.209 The minimal effective dose ranged from 40 to 50 mg/d.217
Low-dose (<0.075%) topical capsaicin has been shown to be effective in the reduction of pain intensity,218,219 improvement in sleep interference,219 quality of life,218 and clinician impression of relief.218,220 The pain reduction occurs within 8 weeks after 4 times per day of application.218 Ultra–low-dose (0.025%) topical capsaicin provided no better pain relief than placebo.221 No PC-RCTs for PDN were identified for high-dose (8%) topical capsaicin.
Oral mexiletine has been shown to be effective in the reduction of pain intensity in 1 trial,222 but no different from placebo in 2 trials223,224; however, each trial experienced small size. One trial noted improvement in sleep interference and nocturnal pain at high doses (675 mg/d),225 with side effects including stomach pain, diarrhea, and nausea.
Dextromethorphan has been shown to be effective in the reduction of pain intensity.165,166 The pain reduction occurs within 4 weeks.166 In both trials, high-dose dextromethorphan was used. The minimal effective dose ranged from 250 to 450 mg/d.165,166 Two PC-RCTs of topical ketamine for DPN found no pain intensity reduction.153,226
Tapentadol has been shown to be effective in the reduction of pain intensity227,228; Vinik et al227 reported improvement in pain in PC-RCTs. The pain reduction occurs within 2–3 weeks.227 The minimal effective dose ranged from 100 mg/d.227,228 Tramadol has been shown to be effective in the reduction of pain intensity and improvement in social and physical functioning in a single PC-RCT.229 The average analgesic dose was 210 mg/d.
Intradermal injection of BoNT-A to the painful foot has been shown to be effective in the reduction of pain intensity,230 pain sensory threshold,231 improvement in sleep interference,230 and quality of life.230 The pain reduction occurs within 1 week.231 Inhaled cannabis reduced spontaneous pain-associated PDN for a short duration in a dose-dependent fashion but had significant negative cognitive effects.232 Nabilone was significantly better than placebo at reducing pain intensity and improving sleep quality.233 Topical clonidine (0.1%) with a daily dose of 3.9 mg applied to painful feet produces significant reduction in pain compared to placebo. In patients with intact peripheral nociceptor function, the response to topical clonidine was significantly greater.234
The combination of 2 effective medications such as nortriptyline/gabapentin142 and morphine/gabapentin141 has been shown to be more effective than either medication alone in the reduction of pain intensity, improvement in sleep interference, quality of life, and mood with reduction in common side effects. The lower side effects were attributable to lower dosages of the individual medications needed to achieve the same or greater pain reduction.
Characterized by radiating pain in one or more dermatomes that may be accompanied by other nerve root irritation symptoms and/or decreased function, the estimated lifetime prevalence estimates is 1.2%–43%.235 In 60% of patients with acute RP (<12 weeks of symptoms), it completely or partially resolves. Unfortunately, about 32% of the patients have pain after 1 year.236 Although this is one of the most common neuropathic pain conditions, most commonly used neuropathic pain medications have either no efficacy or limited efficacy when studied in rigorous RCTs (Table 7).
Two PC-RCTs examining the pain reduction efficacy of pregabalin for chronic RP did not find any benefit as compared to placebo.237,238 Similarly, there was no improvement in quality of life or patient-reported improvement in pain. A trial that alludes to being RCT (Methods section lacks sufficient detail to definitively determine) and suffers from trial design flaws reported a modest benefit of pregabalin for L5 RP but not for lower nerve root distribution RP.239
Gabapentin has been shown to be effective in the reduction of pain intensity and improvement in walking distance in a single PC-RCT,240 but no pain relief was found in a subsequent larger trial.29 Topiramate has been shown to be ineffective in the reduction of pain intensity.241
Amine Reuptake Inhibitors.
Duloxetine has been shown to be effective in the reduction of pain intensity and quality of life in a single PC-RCT.22 The pain reduction occurs within 3 weeks. In a small trial, milnacipran was found to produce a significant decrease in RP compared to placebo, but no secondary outcome such as quality of life, mood, or physical function were improved.242
Amitriptyline, at 25 mg/d,243 was shown to be modestly effective in the reduction of pain intensity and had common side effects in a single PC-RCT. Nortriptyline was found to be effective in pain reduction, but not mood or quality of life in a single trial,18 but had no effect in a subsequent trial.244 Interestingly, in the second trial, the active comparator, morphine, was also ineffective and produced no greater pain relief than the inert placebo.244
Nonsteroidal Anti-inflammatory Drugs.
Indomethacin was found to be effective in the reduction of chronic RP in a PC-RCT,245 but not others.246
Complex Regional Pain Syndrome
CRPS has had different names over the years and with different criteria for diagnosis. The older criteria were proposed by Kozin et al247 in 1981, Veldman et al248 in 1993, and van de Beek et al249 in 2002, none of which were subjected to rigorous testing of its psychometric properties. To be more definitive and consistent in the diagnosis of CRPS, the International Association for the Study of Pain (IASP) and the Budapest criteria were proposed. The IASP criteria250 has a good sensitivity but with low specificity,251 while the Budapest criteria appears to have better characteristics.252 A validation study noted the IASP criteria to have a high diagnostic sensitivity but low specificity,253 resulting in a relatively high rate of false-positive diagnoses and unnecessary treatments. The Budapest criteria, on the other hand, showed the same high sensitivity but with improved specificity253 and is therefore recommended in both clinical and research settings.254 There are 2 types of Budapest criteria, a clinical and a research diagnostic criteria.
Only articles that used the Budapest or IASP criteria to diagnose CRPS were included except 2 articles on bisphosphonates that used the criteria by Kozin et al.247 These 2 studies were discussed because bisphosphonates are an emerging treatment of CRPS. The PC-RCTs on calcitonin also did not employ the IASP or Budapest criteria but were discussed since clinicians need to know the results as some patients inquire about the drug. Exclusion criteria included articles that used the older criteria248,249 other than the one by Kozin et al247 and studies on IV regional or neuraxial treatments.
A study showed IV ketamine to have significantly better pain relief when compared to placebo255 (Table 8). In this study, ketamine was administered over a 4-day period. The dose was given in an individualized stepwise fashion, started at 1.2 µg/kg min (approximately 5 mg/h for a 70-kg patient) to a maximum of 7.2 µg/kg min (30 mg/h for a 70-kg patient). Ketamine was noted to be significantly better in terms of pain relief. However, the difference was gone at 12 weeks, and there was no difference between the treatment groups in their secondary outcomes. Another study showed superiority of ketamine infusion over placebo256 in relieving pain, reducing allodynia, thermal and deep pressure pain thresholds, and improving motor function (Table 8).
A PC-RCT showed 10% topical ketamine to be effective in relieving the allodynia of patients with CRPS264 (Table 8). The plasma levels of ketamine were undetectable, ruling out any systemic effect of the drug. Interestingly, 17 of the 20 patients met the Budapest criteria, while all 20 patients met the IASP criteria.
Oral alendronate, 40 mg every day for 8 weeks, was compared with placebo.265 Alendronate was noted to be superior to placebo in terms of decrease in pain and edema, tolerance to pressure, and joint mobility (Table 9). Alendronate when compared to placebo via the IV route was also noted to be significantly better than placebo.257
A single IV infusion of 60 mg pamidronate resulted in improvements in pain scores, patient’s global assessment of disease score, and functional assessment (Table 8).258 IV clodronate, 300 mg, given daily for 10 consecutive days was noted to have better results (pain scores, clinical global assessment) over placebo.259 Neridronate was also noted to be significantly better than placebo in a multicenter trial.260 The dose was 100 mg neridronate given 4 times over 10 days; improvements were noted with regard to pain on passive motion, McGill Pain Questionnaire, and SF-36. None of the patients had CRPS at 1 year follow-up.
The possibility that immune mechanisms are involved in the pathogenesis of CRPS led investigators to examine the effect of IV immune immunoglobulin (IVIG) on this syndrome. An initial open-label study revealed the efficacy of IVIG in relieving the pain from different chronic pain syndromes, including CRPS.261 Their findings led the authors to proceed to a PC-RCT262 (Table 8). Twelve patients who had CRPS for 6 to 30 months refractory to standard treatment and had pain intensities greater than 4 on an 11-point rating scale were randomized to either IVIG (0.25 g/kg/d, total dose of 0.5 g/kg) or placebo. The intervention was given for 2 consecutive days; the crossover infusion was given 28 days after the initial infusion. Pain diaries were made by the patients daily until 28 days after the last infusion, follow-up was also made 8 weeks later. The IVIG treatment was significantly better than placebo (P < .001); the average pain intensity was 1.6 less after the IVIG treatment and no adverse effects were noted.
Two studies examined the effect of IV magnesium on CRPS.268,269 One study involved 10 patients, 8 received the IV magnesium, while 2 were given saline.268 The patients who had the magnesium infusion had pain relief and improvements in their impairment level and quality of life. Although randomized and double-blinded, the results of the 2 patients who had saline were not presented or analyzed and the results between the 2 treatments were not compared. The same group of investigators later performed a PC-RCT.269 Fifty-nine patients with CRPS type I criteria were randomized into either IV magnesium (29) or placebo (27).269 The magnesium dose was 70 mg/kg for 4 hours a day for 5 consecutive days. Outcome measures included pain relief, impairment score, functional limitation, and quality of life. There was no significant difference between magnesium and placebo in terms of pain relief and impairment score at different time points during the trial. The authors’ conclusion was that magnesium provided insufficient benefit over placebo in patients with CRPS type 1.269
IV Mannitol and IV Parecoxib.
A study compared mannitol, an oxygen radical scavenger with placebo.270 The investigators noted that 10% mannitol in 1 L, given over 4 hours for 5 consecutive days, was not significantly better than placebo in terms of pain relief or any of the outcome measures. A PC-RCT study compared IV parecoxib, 20 mg twice daily for 2 consecutive days, with saline271 using low pressure pain threshold as the primary criteria. The study was stopped after 20 patients because of authors’ difficulty in their recruitment and the absence of improvement in the parecoxib group in any of their primary and secondary outcomes.
Three studies showed superiority of oral steroid over placebo272,273 or piroxicam.274 However, the studies were hampered by the use of physical and radiological findings to diagnose CRPS272,274 or use of the criteria by Kozin et al.247,273 A recent open-label study using the Budapest criteria showed that oral prednisolone did not reduce the average pain intensity in patients with CRPS of greater than 3 months’ duration.275 To date, there is no PC-RCT on oral steroids in CRPS patients diagnosed by the IASP or Budapest criteria.
A crossover study compared gabapentin with placebo266 (Table 9). The dose of gabapentin was started at 600 mg daily then titrated to 600 mg TID, treatment was for 3 weeks followed by a 2-week washout before the crossover portion of the study of another 3 weeks of treatment. There was significantly better pain relief with gabapentin during the first phase, less during the second treatment phase, and the combined phases did not show significant result. Global perceived pain relief showed significant more treatment effect that was more pronounced in the first treatment period. Although sensory deficits were significantly reversed with gabapentin, there was no difference between gabapentin and placebo in the other outcome measures. Interestingly, there was an unexplained increase of pain during the washout period that may have lessened the treatment effect in the second phase of the study. In the clinical setting, most patients are treated for at least several months as long as there is pain relief so we do not know the effect of long-term treatment with gabapentin based on this study.
Another study showed the superiority of gabapentin over placebo in patients with neuropathic pain syndrome, including CRPS.276 Although diagnosis was based on the IASP criteria, the study looked at other neuropathic pain syndromes and the results in the patients who had CRPS were not shown separately. Furthermore, patients who previously did not respond to gabapentin were not enrolled in the study.
A prospective open series showed reduction of pain in patients with CRPS.277 This led investigators to compare morphine (30 mg daily) with or without memantine (40 mg daily) in a PC-RCT.278 The authors showed that only the combination reduced the pain and disability. Unfortunately, the authors used the criteria by van de Beek et al249 to diagnose CRPS.
Tadalafil inhibits phosphodiesterase-5, relaxes smooth muscle, and causes vasodilatation reversing decreased regional blood flow in CRPS. A PC-RCT showed a nonstatistically different temperature change.267 However, there was a statistically and clinically significant reduction in pain with tadalafil at the end of the study (Table 9). The tadalafil dose was 10 mg daily for 4 weeks, then 20 mg for another 8 weeks.
None of the controlled studies on calcitonin employed the psychometrically validated Budapest or IASP criteria.279–283 Two PC-RCT studies on nasal calcitonin showed conflicting results, one noted superiority of calcitonin,279 while the other did not.280 One study used the criteria by Kozin et al247 while the other based their diagnosis only on the presence of swelling and stiffness after a Colles fracture.280 Another randomized study on nasal calcitonin was single-blinded and based their diagnosis on clinical symptoms and physical examination findings; the authors noted no difference between nasal calcitonin to paracetamol.282 Two studies on parenteral calcitonin are not discussed because one study was not blinded,281 while randomization or blinding was not discussed in the other study.283 In summary, one randomized trial showed superiority of calcitonin over placebo,279 while 2 randomized trials showed improvements but no superiority over placebo280 or paracetamol.282 Since the studies on calcitonin did not employ the Budapest or IASP criteria and the diagnosis of CRPS could not be assured in these studies, we cannot determine the real efficacy of calcitonin in this syndrome.
Topical Treatments: DMSO.
Dimethyl sulfoxide (DMSO) is a free radical scavenger; the rationale for its use is the premise that CRPS is induced by an inflammatory response to tissue injury mediated by overproduction of toxic oxygen radicals. A PC-RCT study showed DMSO 50% in fatty cream, given for 2 months, was significantly better than placebo in patients with acute reflex sympathetic dystrophy (RSD).284 Improvements were noted in RSD scores and pain relief at 2-month follow-up. Another study was a randomized, double-dummy controlled trial that compared DMSO with N-acetylcysteine, another free radical scavenger.285 The investigators showed improvements but with equal efficacy between the 2 drugs. Unfortunately, both studies diagnosed RSD with the 1993 criteria by Veldman et al.248
Botulinum Toxin Type A.
The efficacy of subcutaneous BoNT-A in relieving allodynia from chronic neuropathic pain led investigators to perform a PC-RCT on subcutaneous BoNT-A in patients with CRPS.286 BoNT-A was injected at a dose of 5 units per site, half of the dose was injected intradermally while half was injected subcutaneously. The sites ranged from 10 to 40 sites with a total dose of 40–200 units. The outcome measures included several questionnaires and quantitative sensory testing. The study had to be stopped after an interim evaluation showed no relief at 3 or 8 weeks after treatment and 8 of 9 patients considered the treatment to be intolerable and stated that they would not consider the injections as treatment for their pain.286
Tumor Necrosis Factor-α Inhibitors.
A study noted the lack of superiority of infliximab, 5 mg/kg given at weeks 0, 2, and 6 over placebo in terms of total impairment level sum score (redness, swelling, increased temperature, pain dysfunction), inflammatory mediators in the blister fluid, and other outcome measures (Table 8).263
The scope of this review on nonopioid pharmacotherapy was broad and all encompassing for the most common chronic pain syndromes that current pain management physicians treat. A large body of knowledge exists, ranging from case reports to meta-analyses. Considering that 2468 articles were screened and strict inclusion criteria were employed, the paucity of high-quality prospective, blinded, RCTs investigating the pharmacologic therapies that are so commonplace in our field was disappointing (Supplemental Digital Content 3, Table 1, http://links.lww.com/AA/B958). The effect sizes for many treatments were small, including some of those that are FDA approved. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines have reported on the changes in pain scores that are consistent with a “significant” improvement in pain: a change of 30% in numerical pain rating or more. Many of the studies presented here do not provide this level of reduction, yet they have shown statistical significance. Mainstays of treatment, such as NSAIDs, membrane stabilizers, muscle relaxants, and amine reuptake inhibitors, seemed to have positive findings for a few conditions; however, the robustness of pain reduction were modest at best.
The following paragraphs will summarize the findings of positive blinded, controlled, randomized clinical studies on nonopioid medications for chronic pain conditions. For CLBP, nonopioid medications that have been shown to provide significant pain reduction include NSAIDs (naproxen, etoricoxib, valdecoxib, rofecoxib, celecoxib, diclofenac, piroxicam, and indomethacin), ARIs (doxepin, desipramine, nortriptyline, duloxetine, and maprotiline), membrane stabilizers (topiramate), muscle relaxants (only short-term relief for carisoprodol, cyclobenzaprine, and diazepam), mixed ARI/opioid (tramadol, tramadol/acetaminophen, and tapentadol), topical capsaicin cream, BoNT-A, and tanezumab.
For patients with MPS, the following medications have been shown to be efficacious in reducing pain levels: NSAIDs (diclofenac trigger point injections and topical diclofenac sodium patch); muscle relaxants (methocarbamol); topical lidocaine patch; bupivacaine trigger point injections; and BoNT-A. FM has been well studied, and the following nonopioids have been shown to reduce pain scores significantly: ARIs (milnacipran, duloxetine, amitriptyline, fluoxetine, controlled-release paroxetine); membrane stabilizers (pregabalin and gabapentin); muscle relaxants (cyclobenzaprine); mixed ARI/opioid (tramadol/acetaminophen); NMDA antagonists (memantine); opioid antagonists (low-dose naltrexone); and cannabinoids (nabilone).
For the neuropathic pain condition PHN, significant positive findings with regard to pain reduction were shown in membrane stabilizers (pregabalin, gabapentin, and levetiracetam), ARIs (nortriptyline, desipramine, amitriptyline, and fluoxetine), topical capsaicin, lidocaine patch, mixed ARI/opioid (tramadol), and BoNT-A. In PDN, the following nonopioid medications have proven beneficial to improve pain scores: membrane stabilizers (pregabalin, gabapentin, topiramate, lamotrigine, oxcarbazepine, and zonisamide), ARIs (duloxetine, venlafaxine, desipramine, imipramine, amitriptyline, and paroxetine), topical capsaicin, local anesthetics (mexiletine), NMDA antagonists (dextromethorphan), mixed ARI/opioid (tapentadol extended-release and tramadol), BoNT-A, cannabinoids (inhaled cannabis and nabilone), and topical clonidine. Nonopioid medications found to be effective for pain relief in RP are ARIs (duloxetine, amitriptyline, and nortriptyline) and NSAIDs (indomethacin). Finally, for CRPS, the medications reported to reduce pain score intensity include IV ketamine, bisphosphonates (oral alendronate, IV pamidronate, IV clodronate, and neridronate), IVIG, gabapentin, and DMSO. We cannot make concluding statements on calcitonin based on the published studies.
Our review has its limitations. Reviewing and including all of the primary literature per pain condition was simply not feasible within the scope of this review due to the large number of medications included. Furthermore, chronic pain specialists see pain conditions outside of the included syndromes (eg, chronic abdominal pain, entrapment neuropathies, chronic pelvic pain, painful bladder syndrome) and due to space limitations; we were not able to be fully inclusive of all nonmalignant chronic pain syndromes. Instead, we chose to include the most common noncancer pain syndromes seen in most pain management clinics. A large majority of articles were reviewed that had evidence for many pharmacologic agents; however, we only included the higher-quality level evidence of blinded RCTs. We excluded non-English language articles and did not search for abstract-only publications. Due to the narrative nature of this review, reporting of bias was not included or performed.
The evidence base has its limitations as well, which may potentially affect the quality of the included studies. Our inclusion criteria were designed to include only the higher-quality levels of evidence that are inherent in blinded RCTs. However, given that our narrative review methodology did not incorporate assessments or grading of the quality and/or bias of the included individual studies, there does exist a possibility that other aspects of research methodology that affect bias and quality in a negative way could be present in our included studies and thus, this is a limitation of the present review. Populations studied likely had heterogeneity even within a specific pain condition population. Moreover, assessment of “pain outcomes” varies from study to study, which makes it difficult to compare one study to the next, even within a specific pain condition population. Furthermore, many studies were funded by industry; for example, the manufacturer funded the majority of placebo-controlled trials of duloxetine for CLBP and nearly all trials of tramadol and tapentadol.
Even with its substantial societal impact, we have not seen the type of developments in the treatment of the chronic pain that have been garnered in other fields of medicine. There are explanations and challenges in performing transformative pain research that can explain this limited progress. First, pain research is tragically underfunded in both the private and the public sectors. This is distressing on multiple levels and likely distracts talented individuals from pursuing an academic or industry pain research career. Furthermore, although efforts are ongoing to try and improve and prioritize federal funding for pain research, these incremental actions may prove to be insufficient for the enormity of the public health problem. Second, despite chronic pain being the most prevalent public health condition in the United States, the magnitude of the problem is not well recognized by the general public, as indicated by a recent poll of US adults in which only 18% of respondents identified chronic pain as a major public health problem.287 Some recommended changes to improve chronic pain research include an attitude/culture shift, a refocusing and refinement of research approaches and methodology, improved pain research education, and a major investment by the public and private funding sectors.288
More research is needed to determine effective and mechanism-based treatments for the chronic pain syndromes discussed in this review. Studies in which a long-term follow-up is provided would be beneficial in a placebo-controlled, double-blind fashion; however, the ethical implications of long-term placebo use are understood. More research on combinations of pharmacotherapeutics is needed to determine whether incremental or synergistic benefits are seen and whether or not these are sequence reliant. Maintaining rigorous methodology in which the same outcome measures following IMMPACT recommended guidelines (pain outcome measures, quality of life measures, and functioning measures) would likely allow for better consistency and reproducibility, which are of utmost importance in guiding evidence-based care.
Name: Andrea L. Nicol, MD, MSc.
Contribution: This author helped collect data and prepare the manuscript.
Conflicts of Interest: Andrea L. Nicol received a 2017 to 2022 grant from National Institutes of Health K23 (principal investigator [PI]), Central Nervous Pain Amplification in Lumbar Failed Back Surgery Syndrome; and a 2016 to 2018 K-INBRE Developmental Research Project Award (PI), Mechanisms and Modulation of Neuroplasticity in a Rodent Model of Burn Injury and Chronic Pain.
Name: Robert W. Hurley, MD, PhD.
Contribution: This author helped collect the data and prepare the manuscript.
Conflicts of Interest: Robert W. Hurley is currently affiliated with the Department of Anesthesiology and the Clinical Translational Institute, Medical College of Wisconsin (MCW), Milwaukee. He received a 2016 to 2017 grant from the Clinical Translational Research Institute (MCW) (Josh Field, PI; Robert Hurley, co-investigator) functional magnetic resonance imaging in Sickle Cell Disease Pain ($50,000; 2015–2020 AHRQ R01) from the Agency for Healthcare Quality and Research (Chris Harle, PI; Robert Hurley, co-investigator), Designing User-Centered Decision Support Tools for Primary Care Pain Management ($1,943,756; 2015–2016) Faye McBeath Foundation (PI), reducing the transition from prescription opioid abuse to heroin abuse through clinical provider education, $50,000; 2013–2016 Pfizer, Inc (PI; Christopher Harle, co-PI); An Integrative and Sustainable Approach to Pain Management in Primary Care, $499,997; 2015–2016 St Jude Medical, Education of Multidisciplinary Pain Fellows (PI) MCW; 2015–2016 Medtronic Inc, Education of Multidisciplinary Pain Fellows (PI) MCW; 2014–2015 Boston Scientific, Education of Multidisciplinary Pain Fellows (PI) UF; 2014–2015 Medtronic, Education of Multidisciplinary Pain Fellows (PI) UF.
Name: Honorio T. Benzon, MD.
Contribution: This author helped collect the data and prepare the manuscript.
Conflicts of Interest: None.
This manuscript was handled by: Jianren Mao, MD, PhD.
1. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. 2011.Washington, DC: The National Academies Press.
2. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. MMWR Recomm Rep. 2016;65:1–49.
3. Levy B, Paulozzi L, Mack KA, Jones CM. Trends in opioid analgesic-prescribing rates by specialty, U.S., 2007-2012. Am J Prev Med. 2015;49:409–413.
4. Paulozzi LJ, Mack KA, Hockenberry JM; Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC. Vital signs: variation among States in prescribing of opioid pain relievers and benzodiazepines—United States, 2012. MMWR Morb Mortal Wkly Rep. 2014;63:563–568.
5. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162:276–286.
6. Chou R, Huffman LH; American Pain Society; American College of Physicians. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007;147:505–514.
7. Bedaiwi MK, Sari I, Wallis D, et al. Clinical efficacy of celecoxib compared to acetaminophen in chronic nonspecific low back pain: results of a randomized controlled trial. Arthritis Care Res (Hoboken). 2016;68:845–852.
8. Hickey RF. Chronic low back pain: a comparison of diflunisal with paracetamol. N Z Med J. 1982;95:312–314.
9. Berry H, Bloom B, Hamilton EB, Swinson DR. Naproxen sodium, diflunisal, and placebo in the treatment of chronic back pain. Ann Rheum Dis. 1982;41:129–132.
10. Birbara CA, Puopolo AD, Munoz DR, et al.; Etoricoxib Protocol 042 Study Group. Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability—a randomized, placebo-controlled, 3-month trial. J Pain. 2003;4:307–315.
11. Coats TL, Borenstein DG, Nangia NK, Brown MT. Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial. Clin Ther. 2004;26:1249–1260.
12. Katz N, Ju WD, Krupa DA, et al. Efficacy and safety of rofecoxib in patients with chronic low back pain: results from two 4-week, randomized, placebo-controlled, parallel-group, double-blind trials. Spine (Phila Pa 1976). 2003;28:851–858.
13. Pallay RM, Seger W, Adler JL, et al. Etoricoxib reduced pain and disability and improved quality of life in patients with chronic low back pain: a 3 month, randomized, controlled trial. Scand J Rheumatol. 2004;33:257–266.
14. Videman T, Osterman K. Double-blind parallel study of piroxicam versus indomethacin in the treatment of low back pain. Ann Clin Res. 1984;16:156–160.
15. Zerbini C, Ozturk ZE, Grifka J, et al.; Etoricoxib CLBP Study Group. Efficacy of etoricoxib 60 mg/day and diclofenac 150 mg/day in reduction of pain and disability in patients with chronic low back pain: results of a 4-week, multinational, randomized, double-blind study. Curr Med Res Opin. 2005;21:2037–2049.
16. Ward N, Bokan JA, Phillips M, Benedetti C, Butler S, Spengler D. Antidepressants in concomitant chronic back pain and depression: doxepin and desipramine compared. J Clin Psychiatry. 1984;45:54–59.
17. Ward NG. Tricyclic antidepressants for chronic low-back pain. Mechanisms of action and predictors of response. Spine (Phila Pa 1976). 1986;11:661–665.
18. Atkinson JH, Slater MA, Williams RA, et al. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain. Pain. 1998;76:287–296.
19. Atkinson JH, Slater MA, Capparelli EV, et al. Efficacy of noradrenergic and serotonergic antidepressants in chronic back pain: a preliminary concentration-controlled trial. J Clin Psychopharmacol. 2007;27:135–142.
20. Alcoff J, Jones E, Rust P, Newman R. Controlled trial of imipramine for chronic low back pain. J Fam Pract. 1982;14:841–846.
21. Konno S, Oda N, Ochiai T, Alev L. Randomized, double-blind, placebo-controlled phase iii trial of duloxetine monotherapy in Japanese patients with chronic low back pain. Spine (Phila Pa 1976). 2016;41:1709–1717.
22. Schukro RP, Oehmke MJ, Geroldinger A, Heinze G, Kress HG, Pramhas S. Efficacy of duloxetine in chronic low back pain with a neuropathic component: a randomized, double-blind, placebo-controlled crossover trial. Anesthesiology. 2016;124:150–158.
23. Skljarevski V, Desaiah D, Liu-Seifert H, et al. Efficacy and safety of duloxetine in patients with chronic low back pain. Spine (Phila Pa 1976). 2010;35:E578–E585.
24. Skljarevski V, Zhang S, Desaiah D, et al. Duloxetine versus placebo in patients with chronic low back pain: a 12-week, fixed-dose, randomized, double-blind trial. J Pain. 2010;11:1282–1290.
25. Skljarevski V, Ossanna M, Liu-Seifert H, et al. A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain. Eur J Neurol. 2009;16:1041–1048.
26. Atkinson JH, Slater MA, Wahlgren DR, et al. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Pain. 1999;83:137–145.
27. Dickens C, Jayson M, Sutton C, Creed F. The relationship between pain and depression in a trial using paroxetine in sufferers of chronic low back pain. Psychosomatics. 2000;41:490–499.
28. Katz J, Pennella-Vaughan J, Hetzel RD, Kanazi GE, Dworkin RH. A randomized, placebo-controlled trial of bupropion sustained release in chronic low back pain. J Pain. 2005;6:656–661.
29. Atkinson JH, Slater MA, Capparelli EV, et al. A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component. Pain. 2016;157:1499–1507.
30. Sakai Y, Ito K, Hida T, Ito S, Harada A. Pharmacological management of chronic low back pain in older patients: a randomized controlled trial of the effect of pregabalin and opioid administration. Eur Spine J. 2015;24:1309–1317.
31. Romanò CL, Romanò D, Bonora C, Mineo G. Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain. J Orthop Traumatol. 2009;10:185–191.
32. Muehlbacher M, Nickel MK, Kettler C, et al. Topiramate in treatment of patients with chronic low back pain: a randomized, double-blind, placebo-controlled study. Clin J Pain. 2006;22:526–531.
33. Baratta RR. A double-blind comparative study of carisoprodol, propoxyphene, and placebo in the management of low back syndrome. Curr Ther Res Clin Exp. 1976;20:233–240.
34. Brown BR Jr, Womble J. Cyclobenzaprine in intractable pain syndromes with muscle spasm. JAMA. 1978;240:1151–1152.
35. Basmajian JV. Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical and laboratory studies. Arch Phys Med Rehabil. 1978;59:58–63.
36. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother. 2010;11:1787–1804.
37. Lee JH, Lee CS; Ultracet ER Study Group. A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of the extended-release tramadol hydrochloride/acetaminophen fixed-dose combination tablet for the treatment of chronic low back pain. Clin Ther. 2013;35:1830–1840.
38. Peloso PM, Fortin L, Beaulieu A, Kamin M, Rosenthal N; Protocol TRP-CAN-1 Study Group. Analgesic efficacy and safety of tramadol/ acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial. J Rheumatol. 2004;31:2454–2463.
39. Ruoff GE, Rosenthal N, Jordan D, Karim R, Kamin M; Protocol CAPSS-112 Study Group. Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter, randomized, double-blind, placebo-controlled outpatient study. Clin Ther. 2003;25:1123–1141.
40. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol. 2000;27:772–778.
41. Vorsanger GJ, Xiang J, Gana TJ, Pascual ML, Fleming RR. Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain. J Opioid Manag. 2008;4:87–97.
42. Schiphorst Preuper HR, Geertzen JH, van Wijhe M, et al. Do analgesics improve functioning in patients with chronic low back pain? An explorative triple-blinded RCT. Eur Spine J. 2014;23:800–806.
43. O’Donnell JB, Ekman EF, Spalding WM, Bhadra P, McCabe D, Berger MF. The effectiveness of a weak opioid medication versus a cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug in treating flare-up of chronic low-back pain: results from two randomized, double-blind, 6-week studies. J Int Med Res. 2009;37:1789–1802.
44. Baron R, Likar R, Martin-Mola E, et al. Effectiveness of tapentadol prolonged release (PR) compared with oxycodone/naloxone PR for the management of severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 Study. Pain Pract. 2016;16:580–599.
45. Baron R, Martin-Mola E, Müller M, Dubois C, Falke D, Steigerwald I. Effectiveness and safety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study. Pain Pract. 2015;15:455–470.
46. Mullican WS, Lacy JR; TRAMAP-ANAG-006 Study Group. Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther. 2001;23:1429–1445.
47. Tetsunaga T, Tetsunaga T, Tanaka M, Ozaki T. Efficacy of tramadol-acetaminophen tablets in low back pain patients with depression. J Orthop Sci. 2015;20:281–286.
48. Hashmi JA, Baliki MN, Huang L, et al. Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study. Mol Pain. 2012;8:29.
49. Keitel W, Frerick H, Kuhn U, Schmidt U, Kuhlmann M, Bredehorst A. Capsicum pain plaster in chronic non-specific low back pain. Arzneimittelforschung. 2001;51:896–903.
50. Foster L, Clapp L, Erickson M, Jabbari B. Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology. 2001;56:1290–1293.
51. Kleinböhl D, Görtelmeyer R, Bender HJ, Hölzl R. Amantadine sulfate reduces experimental sensitization and pain in chronic back pain patients. Anesth Analg. 2006;102:840–847.
52. Katz N, Borenstein DG, Birbara C, et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain. 2011;152:2248–2258.
53. Kivitz AJ, Gimbel JS, Bramson C, et al. Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain. Pain. 2013;154:1009–1021.
54. Soares A, Andriolo RB, Atallah AN, da Silva EM. Botulinum toxin for myofascial pain syndromes in adults. Cochrane Database Syst Rev. 2014:Cd007533.
55. Frost A. Diclofenac versus lidocaine as injection therapy in myofascial pain. Scand J Rheumatol. 1986;15:153–156.
56. Hsieh LF, Hong CZ, Chern SH, Chen CC. Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius. J Pain Symptom Manage. 2010;39:116–125.
57. Schreiber S, Vinokur S, Shavelzon V, Pick CG, Zahavi E, Shir Y. A randomized trial of fluoxetine versus amitriptyline in musculo-skeletal pain. Isr J Psychiatry Relat Sci. 2001;38:88–94.
58. Valtonen EJ. A double-blind trial of methocarbamol versus placebo in painful muscle spasm. Curr Med Res Opin. 1975;3:382–385.
59. Affaitati G, Fabrizio A, Savini A, et al. A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther. 2009;31:705–720.
60. Lin YC, Kuan TS, Hsieh PC, Yen WJ, Chang WC, Chen SM. Therapeutic effects of lidocaine patch on myofascial pain syndrome of the upper trapezius: a randomized, double-blind, placebo-controlled study. Am J Phys Med Rehabil. 2012;91:871–882.
61. Cho JH, Brodsky M, Kim EJ, et al. Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: a double-blinded randomized trial. Pain Med. 2012;13:965–970.
62. Kim DH, Yoon KB, Park S, et al. Comparison of NSAID patch given as monotherapy and NSAID patch in combination with transcutaneous electric nerve stimulation, a heating pad, or topical capsaicin in the treatment of patients with myofascial pain syndrome of the upper trapezius: a pilot study. Pain Med. 2014;15:2128–2138.
63. De Andrés J, Adsuara VM, Palmisani S, Villanueva V, López-Alarcón MD. A double-blind, controlled, randomized trial to evaluate the efficacy of botulinum toxin for the treatment of lumbar myofascial pain in humans. Reg Anesth Pain Med. 2010;35:255–260.
64. Braker C, Yariv S, Adler R, Badarny S, Eisenberg E. The analgesic effect of botulinum-toxin A on postwhiplash neck pain. Clin J Pain. 2008;24:5–10.
65. Cheshire WP, Abashian SW, Mann JD. Botulinum toxin in the treatment of myofascial pain syndrome. Pain. 1994;59:65–69.
66. Freund BJ, Schwartz M. Treatment of whiplash associated neck pain [corrected] with botulinum toxin-A: a pilot study. J Rheumatol. 2000;27:481–484.
67. Miller D, Richardson D, Eisa M, Bajwa RJ, Jabbari B. Botulinum neurotoxin-A for treatment of refractory neck pain: a randomized, double-blind study. Pain Med. 2009;10:1012–1017.
68. Nicol AL, Wu II, Ferrante FM. Botulinum toxin type A injections for cervical and shoulder girdle myofascial pain using an enriched protocol design. Anesth Analg. 2014;118:1326–1335.
69. Kamanli A, Kaya A, Ardicoglu O, Ozgocmen S, Zengin FO, Bayik Y. Comparison of lidocaine injection, botulinum toxin injection, and dry needling to trigger points in myofascial pain syndrome. Rheumatol Int. 2005;25:604–611.
70. Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain. 2000;85:101–105.
71. Ferrante FM, Bearn L, Rothrock R, King L. Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A. Anesthesiology. 2005;103:377–383.
72. Kwanchuay P, Petchnumsin T, Yiemsiri P, Pasuk N, Srikanok W, Hathaiareerug C. Efficacy and safety of single Botulinum toxin type A (Botox®) injection for relief of upper trapezius myofascial trigger point: a randomized, double-blind, placebo-controlled study. J Med Assoc Thai. 2015;98:1231–1236.
73. Lew HL, Lee EH, Castaneda A, Klima R, Date E. Therapeutic use of botulinum toxin type A in treating neck and upper-back pain of myofascial origin: a pilot study. Arch Phys Med Rehabil. 2008;89:75–80.
74. Ojala T, Arokoski JP, Partanen J. The effect of small doses of botulinum toxin A on neck-shoulder myofascial pain syndrome: a double-blind, randomized, and controlled crossover trial. Clin J Pain. 2006;22:90–96.
75. Padberg M, de Bruijn SF, Tavy DL. Neck pain in chronic whiplash syndrome treated with botulinum toxin. A double-blind, placebo-controlled clinical trial. J Neurol. 2007;254:290–295.
76. Qerama E, Fuglsang-Frederiksen A, Kasch H, Bach FW, Jensen TS. A double-blind, controlled study of botulinum toxin A in chronic myofascial pain. Neurology. 2006;67:241–245.
77. Wheeler AH, Goolkasian P, Gretz SS. A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome. Spine (Phila Pa 1976). 1998;23:1662–1666.
78. Graboski CL, Gray DS, Burnham RS. Botulinum toxin A versus bupivacaine trigger point injections for the treatment of myofascial pain syndrome: a randomised double blind crossover study. Pain. 2005;118:170–175.
79. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311:1547–1555.
80. Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in primary fibromyalgia syndrome: a double blind, placebo controlled trial. J Rheumatol. 1989;16:527–532.
81. Russell IJ, Fletcher EM, Michalek JE, McBroom PC, Hester GG. Treatment of primary fibrositis/fibromyalgia syndrome with ibuprofen and alprazolam. A double-blind, placebo-controlled study. Arthritis Rheum. 1991;34:552–560.
82. Staud R, Lucas YE, Price DD, Robinson ME. Effects of milnacipran on clinical pain and hyperalgesia of patients with fibromyalgia: results of a 6-week randomized controlled trial. J Pain. 2015;16:750–759.
83. Arnold LM, Gendreau RM, Palmer RH, Gendreau JF, Wang Y. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:2745–2756.
84. Arnold LM, Palmer RH, Gendreau RM, Chen W. Relationships among pain, depressed mood, and global status in fibromyalgia patients: post hoc analyses of a randomized, placebo-controlled trial of milnacipran. Psychosomatics. 2012;53:371–379.
85. Branco JC, Cherin P, Montagne A, Bouroubi A; Multinational Coordinator Study Group. Longterm therapeutic response to milnacipran treatment for fibromyalgia. A European 1-year extension study following a 3-month study. J Rheumatol. 2011;38:1403–1412.
86. Branco JC, Zachrisson O, Perrot S, Mainguy Y; Multinational Coordinator Study Group. A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. J Rheumatol. 2010;37:851–859.
87. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008;30:1988–2004.
88. Geisser ME, Palmer RH, Gendreau RM, Wang Y, Clauw DJ. A pooled analysis of two randomized, double-blind, placebo-controlled trials of milnacipran monotherapy in the treatment of fibromyalgia. Pain Pract. 2011;11:120–131.
89. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol. 2005;32:1975–1985.
90. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:398–409.
91. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Hum Psychopharmacol. 2004;19(suppl 1):S27–S35.
92. Arnold LM, Clauw D, Wang F, Ahl J, Gaynor PJ, Wohlreich MM. Flexible dosed duloxetine in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2010;37:2578–2586.
93. Arnold LM, Hudson JI, Wang F, et al. Comparisons of the efficacy and safety of duloxetine for the treatment of fibromyalgia in patients with versus without major depressive disorder. Clin J Pain. 2009;25:461–468.
94. Arnold LM, Clauw DJ, Wohlreich MM, et al. Efficacy of duloxetine in patients with fibromyalgia: pooled analysis of 4 placebo-controlled clinical trials. Prim Care Companion J Clin Psychiatry. 2009;11:237–244.
95. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974–2984.
96. Arnold LM, Pritchett YL, D’Souza DN, Kajdasz DK, Iyengar S, Wernicke JF. Duloxetine for the treatment of fibromyalgia in women: pooled results from two randomized, placebo-controlled clinical trials. J Womens Health (Larchmt). 2007;16:1145–1156.
97. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5–15.
98. Chappell AS, Littlejohn G, Kajdasz DK, Scheinberg M, D’Souza DN, Moldofsky H. A 1-year safety and efficacy study of duloxetine in patients with fibromyalgia. Clin J Pain. 2009;25:365–375.
99. Mease PJ, Russell IJ, Kajdasz DK, et al. Long-term safety, tolerability, and efficacy of duloxetine in the treatment of fibromyalgia. Semin Arthritis Rheum. 2010;39:454–464.
100. Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain. 2008;136:432–444.
101. Arnold LM, Zhang S, Pangallo BA. Efficacy and safety of duloxetine 30 mg/d in patients with fibromyalgia: a randomized, double-blind, placebo-controlled study. Clin J Pain. 2012;28:775–781.
102. Murakami M, Osada K, Mizuno H, Ochiai T, Alev L, Nishioka K. A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients. Arthritis Res Ther. 2015;17:224.
103. Chappell AS, Bradley LA, Wiltse C, Detke MJ, D’Souza DN, Spaeth M. A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia. Int J Gen Med. 2008;1:91–102.
104. Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum. 1994;37:32–40.
105. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852–1859.
106. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986;29:1371–1377.
107. Hannonen P, Malminiemi K, Yli-Kerttula U, Isomeri R, Roponen P. A randomized, double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder. Br J Rheumatol. 1998;37:1279–1286.
108. Heymann RE, Helfenstein M, Feldman D. A double-blind, randomized, controlled study of amitriptyline, nortriptyline and placebo in patients with fibromyalgia. An analysis of outcome measures. Clin Exp Rheumatol. 2001;19:697–702.
109. Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo-controlled study. Arthritis Rheum. 1986;29:655–659.
110. Patkar AA, Masand PS, Krulewicz S, et al. A randomized, controlled, trial of controlled release paroxetine in fibromyalgia. Am J Med. 2007;120:448–454.
111. Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9:792–805.
112. Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol. 2008;35:502–514.
113. Crofford LJ, Rowbotham MC, Mease PJ, et al.; Pregabalin 1008-105 Study Group. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264–1273.
114. Ohta H, Oka H, Usui C, Ohkura M, Suzuki M, Nishioka K. A randomized, double-blind, multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia. Arthritis Res Ther. 2012;14:R217.
115. Arnold LM, Sarzi-Puttini P, Arsenault P, et al. Efficacy and safety of pregabalin in patients with fibromyalgia and comorbid depression taking concurrent antidepressant medication: a randomized, placebo-controlled study. J Rheumatol. 2015;42:1237–1244.
116. Clair A, Emir B. The safety and efficacy of pregabalin for treating subjects with fibromyalgia and moderate or severe baseline widespread pain. Curr Med Res Opin. 2016;32:601–609.
117. Pauer L, Winkelmann A, Arsenault P, et al.; A0081100 Investigators. An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia. J Rheumatol. 2011;38:2643–2652.
118. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. Pain. 2016;157:1532–1540.
119. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56:1336–1344.
120. Quimby LG, Gratwick GM, Whitney CD, Block SR. A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. J Rheumatol Suppl. 1989;19:140–143.
121. Bennett RM, Gatter RA, Campbell SM, Andrews RP, Clark SR, Scarola JA. A comparison of cyclobenzaprine and placebo in the management of fibrositis. A double-blind controlled study. Arthritis Rheum. 1988;31:1535–1542.
122. Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. J Rheumatol. 1991;18:452–454.
123. Vaerøy H, Abrahamsen A, Førre O, Kåss E. Treatment of fibromyalgia (fibrositis syndrome): a parallel double blind trial with carisoprodol, paracetamol and caffeine (Somadril comp) versus placebo. Clin Rheumatol. 1989;8:245–250.
124. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med. 2003;114:537–545.
125. Noppers I, Niesters M, Swartjes M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. 2011;15:942–949.
126. Olivan-Blázquez B, Herrera-Mercadal P, Puebla-Guedea M, et al. Efficacy of memantine in the treatment of fibromyalgia: a double-blind, randomised, controlled trial with 6-month follow-up. Pain. 2014;155:2517–2525.
127. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65:529–538.
128. Vlainich R, Issy AM, Gerola LR, Sakata RK. Effect of intravenous lidocaine on manifestations of fibromyalgia. Pain Pract. 2010;10:301–305.
129. Vlainich R, Issy AM, Sakata RK. Effect of intravenous lidocaine associated with amitriptyline on pain relief and plasma serotonin, norepinephrine, and dopamine concentrations in fibromyalgia. Clin J Pain. 2011;27:285–288.
130. Albertoni Giraldes AL, Salomão R, Leal PD, Brunialti MK, Sakata RK. Effect of intravenous lidocaine combined with amitriptyline on pain intensity, clinical manifestations and the concentrations of IL-1, IL-6 and IL-8 in patients with fibromyalgia: a randomized double-blind study. Int J Rheum Dis. 2016;19:946–953.
131. Clark S, Tindall E, Bennett RM. A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis. J Rheumatol. 1985;12:980–983.
132. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9:164–173.
133. Young L. Post-herpetic neuralgia: a review of advances in treatment and prevention. J Drugs Dermatol. 2006;5:938–941.
134. Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2003;60:1274–1283.
135. Sabatowski R, Gálvez R, Cherry DA, et al.; 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004;109:26–35.
136. Stacey BR, Barrett JA, Whalen E, Phillips KF, Rowbotham MC. Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain. 2008;9:1006–1017.
137. Gilron I, Wajsbrot D, Therrien F, Lemay J. Pregabalin for peripheral neuropathic pain: a multicenter, enriched enrollment randomized withdrawal placebo-controlled trial. Clin J Pain. 2011;27:185–193.
138. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005;115:254–263.
139. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837–1842.
140. Rice AS, Maton S; Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–224.
141. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–1334.
142. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009;374:1252–1261.
143. Zhang L, Rainka M, Freeman R, et al. A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of gabapentin enacarbil in subjects with neuropathic pain associated with postherpetic neuralgia (PXN110748). J Pain. 2013;14:590–603.
144. Wallace MS, Irving G, Cowles VE. Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicentre study. Clin Drug Investig. 2010;30:765–776.
145. Sang CN, Sathyanarayana R, Sweeney M; DM-1796 Study Investigators. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281–288.
146. Irving G, Jensen M, Cramer M, et al. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial. Clin J Pain. 2009;25:185–192.
147. Demant DT, Lund K, Vollert J, et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain. 2014;155:2263–2273.
148. Rowbotham MC, Manville NS, Ren J. Pilot tolerability and effectiveness study of levetiracetam for postherpetic neuralgia. Neurology. 2003;61:866–867.
149. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998;51:1166–1171.
150. Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther. 1990;47:305–312.
151. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59:1015–1021.
152. Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology. 1982;32:671–673.
153. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2005;103:140–146.
154. Ho KY, Huh BK, White WD, Yeh CC, Miller EJ. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain. 2008;24:51–55.
155. Rowbotham MC, Reisner LA, Davies PS, Fields HL. Treatment response in antidepressant-naïve postherpetic neuralgia patients: double-blind, randomized trial. J Pain. 2005;6:741–746.
156. Backonja M, Wallace MS, Blonsky ER, et al.; NGX-4010 C116 Study Group. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 2008;7:1106–1112.
157. Webster LR, Malan TP, Tuchman MM, Mollen MD, Tobias JK, Vanhove GF. A multicenter, randomized, double-blind, controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. J Pain. 2010;11:972–982.
158. Backonja MM, Malan TP, Vanhove GF, Tobias JK; C102/106 Study Group. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010;11:600–608.
159. Irving GA, Backonja MM, Dunteman E, et al.; NGX-4010 C117 Study Group. A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med. 2011;12:99–109.
160. Watson CP, Tyler KL, Bickers DR, Millikan LE, Smith S, Coleman E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther. 1993;15:510–526.
161. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996;65:39–44.
162. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain. 1999;80:533–538.
163. Galer BS, Jensen MP, Ma T, Davies PS, Rowbotham MC. The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain. 2002;18:297–301.
164. Demant DT, Lund K, Finnerup NB, et al. Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype: a randomised, double-blind, and placebo-controlled, phenotype panel study. Pain. 2015;156:2234–2244.
165. Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology. 2002;96:1053–1061.
166. Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology. 1997;48:1212–1218.
167. Brill S, Sedgwick PM, Hamann W, Di Vadi PP. Efficacy of intravenous magnesium in neuropathic pain. Br J Anaesth. 2002;89:711–714.
168. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003;104:323–331.
169. Saxena AK, Nasare N, Jain S, et al. A randomized, prospective study of efficacy and safety of oral tramadol in the management of post-herpetic neuralgia in patients from north India. Pain Pract. 2013;13:264–275.
170. Shackelford S, Rauck R, Quessy S, Blum D, Hodge R, Philipson R. A randomized, double-blind, placebo-controlled trial of a selective COX-2 inhibitor, GW406381, in patients with postherpetic neuralgia. J Pain. 2009;10:654–660.
171. Ahmed SU, Zhang Y, Chen L, et al. Effect of 1.5% topical diclofenac on clinical neuropathic pain. Anesthesiology. 2015;123:191–198.
172. Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH. Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and placebo. Clin Pharmacol Ther. 1988;43:363–371.
173. Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D. Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med. 2010;11:1827–1833.
174. Apalla Z, Sotiriou E, Lallas A, Lazaridou E, Ioannides D. Botulinum toxin A in postherpetic neuralgia: a parallel, randomized, double-blind, single-dose, placebo-controlled trial. Clin J Pain. 2013;29:857–864.
175. Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988;38:1427–1432.
176. Rathur HM, Boulton AJ. Recent advances in the diagnosis and management of diabetic neuropathy. J Bone Joint Surg Br. 2005;87:1605–1610.
177. Paisley A, Abbott C, van Schie C, Boulton A. A comparison of the Neuropen against standard quantitative sensory-threshold measures for assessing peripheral nerve function. Diabet Med. 2002;19:400–405.
178. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004;110:628–638.
179. Tölle T, Freynhagen R, Versavel M, Trostmann U, Young JP Jr. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain. 2008;12:203–213.
180. Satoh J, Yagihashi S, Baba M, et al. Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial. Diabet Med. 2011;28:109–116.
181. Moon DE, Lee DI, Lee SC, et al. Efficacy and tolerability of pregabalin using a flexible, optimized dose schedule in Korean patients with peripheral neuropathic pain: a 10-week, randomized, double-blind, placebo-controlled, multicenter study. Clin Ther. 2010;32:2370–2385.
182. Guan Y, Ding X, Cheng Y, et al. Efficacy of pregabalin for peripheral neuropathic pain: results of an 8-week, flexible-dose, double-blind, placebo-controlled study conducted in China. Clin Ther. 2011;33:159–166.
183. Richter RW, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp LE. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain. 2005;6:253–260.
184. Rauck R, Makumi CW, Schwartz S, et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13:485–496.
185. Ziegler D, Duan WR, An G, Thomas JW, Nothaft W. A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain. 2015;156:2013–2020.
186. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63:2104–2110.
187. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280:1831–1836.
188. Solak Y, Biyik Z, Atalay H, et al. Pregabalin versus gabapentin in the treatment of neuropathic pruritus in maintenance haemodialysis patients: a prospective, crossover study. Nephrology (Carlton). 2012;17:710–717.
189. Gorson KC, Schott C, Herman R, Ropper AH, Rand WM. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry. 1999;66:251–252.
190. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25:81–104.
191. Sandercock D, Cramer M, Biton V, Cowles VE. A gastroretentive gabapentin formulation for the treatment of painful diabetic peripheral neuropathy: efficacy and tolerability in a double-blind, randomized, controlled clinical trial. Diabetes Res Clin Pract. 2012;97:438–445.
192. Raskin P, Donofrio PD, Rosenthal NR, et al.; CAPSS-141 Study Group. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004;63:865–873.
193. Thienel U, Neto W, Schwabe SK, Vijapurkar U; Topiramate Diabetic Neuropathic Pain Study Group. Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials. Acta Neurol Scand. 2004;110:221–231.
194. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology. 2001;57:505–509.
195. Vinik AI, Tuchman M, Safirstein B, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain. 2007;128:169–179.
196. Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain. 2005;9:543–554.
197. Beydoun A, Kobetz SA, Carrazana EJ. Efficacy of oxcarbazepine in the treatment of painful diabetic neuropathy. Clin J Pain. 2004;20:174–178.
198. Grosskopf J, Mazzola J, Wan Y, Hopwood M. A randomized, placebo-controlled study of oxcarbazepine in painful diabetic neuropathy. Acta Neurol Scand. 2006;114:177–180.
199. Atli A, Dogra S. Zonisamide in the treatment of painful diabetic neuropathy: a randomized, double-blind, placebo-controlled pilot study. Pain Med. 2005;6:225–234.
200. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116:109–118.
201. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6:346–356.
202. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67:1411–1420.
203. Gao Y, Guo X, Han P, et al. Treatment of patients with diabetic peripheral neuropathic pain in China: a double-blind randomised trial of duloxetine vs. placebo. Int J Clin Pract. 2015;69:957–966.
204. Yasuda H, Hotta N, Nakao K, Kasuga M, Kashiwagi A, Kawamori R. Superiority of duloxetine to placebo in improving diabetic neuropathic pain: results of a randomized controlled trial in Japan. J Diabetes Investig. 2011;2:132–139.
205. Gao Y, Ning G, Jia WP, et al. Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China. Chin Med J (Engl). 2010;123:3184–3192.
206. Raskin J, Wang F, Pritchett YL, Goldstein DJ. Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain Med. 2006;7:373–385.
207. Yasuda H, Hotta N, Kasuga M, et al. Efficacy and safety of 40 mg or 60 mg duloxetine in Japanese adults with diabetic neuropathic pain: results from a randomized, 52-week, open-label study. J Diabetes Investig. 2016;7:100–108.
208. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706.
209. Kadiroglu AK, Sit D, Kayabasi H, Tuzcu AK, Tasdemir N, Yilmaz ME. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. J Diabetes Complications. 2008;22:241–245.
210. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326:1250–1256.
211. Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45:3–9.
212. Kvinesdal B, Molin J, Frøland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984;251:1727–1730.
213. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37:589–596.
214. Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindström T, Thorell LH. A comparison of amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997;13:313–323.
215. Boyle J, Eriksson ME, Gribble L, et al. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care. 2012;35:2451–2458.
216. Sindrup SH, Gram LF, Brøsen K, Eshøj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42:135–144.
217. Sindrup SH, Grodum E, Gram LF, Beck-Nielsen H. Concentration-response relationship in paroxetine treatment of diabetic neuropathy symptoms: a patient-blinded dose-escalation study. Ther Drug Monit. 1991;13:408–414.
218. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group. Arch Intern Med. 1991;151:2225–2229.
219. Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care. 1992;15:159–165.
220. Tandan R, Lewis GA, Krusinski PB, Badger GB, Fries TJ. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care. 1992;15:8–14.
221. Kulkantrakorn K, Lorsuwansiri C, Meesawatsom P. 0.025% capsaicin gel for the treatment of painful diabetic neuropathy: a randomized, double-blind, crossover, placebo-controlled trial. Pain Pract. 2013;13:497–503.
222. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet. 1988;1:9–11.
223. Stracke H, Meyer UE, Schumacher HE, Federlin K. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care. 1992;15:1550–1555.
224. Wright JM, Oki JC, Graves L III. Mexiletine in the symptomatic treatment of diabetic peripheral neuropathy. Ann Pharmacother. 1997;31:29–34.
225. Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. The Mexiletine Study Group. Diabetes Care. 1997;20:1594–1597.
226. Mahoney JM, Vardaxis V, Moore JL, Hall AM, Haffner KE, Peterson MC. Topical ketamine cream in the treatment of painful diabetic neuropathy: a randomized, placebo-controlled, double-blind initial study. J Am Podiatr Med Assoc. 2012;102:178–183.
227. Vinik AI, Shapiro DY, Rauschkolb C, et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care. 2014;37:2302–2309.
228. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27:151–162.
229. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842–1846.
230. Yuan RY, Sheu JJ, Yu JM, et al. Botulinum toxin for diabetic neuropathic pain: a randomized double-blind crossover trial. Neurology. 2009;72:1473–1478.
231. Chen WT, Yuan RY, Chiang SC, et al. OnabotulinumtoxinA improves tactile and mechanical pain perception in painful diabetic polyneuropathy. Clin J Pain. 2013;29:305–310.
232. Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015;16:616–627.
233. Toth C, Mawani S, Brady S, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain. 2012;153:2073–2082.
234. Campbell CM, Kipnes MS, Stouch BC, et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain. 2012;153:1815–1823.
235. Konstantinou K, Dunn KM. Sciatica: review of epidemiological studies and prevalence estimates. Spine (Phila Pa 1976). 2008;33:2464–2472.
236. Weber H, Holme I, Amlie E. The natural course of acute sciatica with nerve root symptoms in a double-blind placebo-controlled trial evaluating the effect of piroxicam. Spine (Phila Pa 1976). 1993;18:1433–1438.
237. Mathieson S, Maher CG, McLachlan AJ, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376:1111–1120.
238. Malik KM, Nelson AM, Avram MJ, Robak SL, Benzon HT. Efficacy of pregabalin in the treatment of radicular pain: results of a controlled trial. Anesth Pain Med. 2015;5:e28110.
239. Takahashi N, Arai I, Kayama S, et al. Therapeutic efficacy of pregabalin in patients with leg symptoms due to lumbar spinal stenosis. Fukushima J Med Sci. 2014;60:35–42.
240. Yaksi A, Ozgönenel L, Ozgönenel B. The efficiency of gabapentin therapy in patients with lumbar spinal stenosis. Spine (Phila Pa 1976). 2007;32:939–942.
241. Khoromi S, Patsalides A, Parada S, Salehi V, Meegan JM, Max MB. Topiramate in chronic lumbar radicular pain. J Pain. 2005;6:829–836.
242. Marks DM, Pae CU, Patkar AA. A double-blind, placebo-controlled, parallel-group pilot study of milnacipran for chronic radicular pain (sciatica) associated with lumbosacral disc disease. Prim Care Companion CNS Disord. 2014;16(4).
243. Vanelderen P, Van Zundert J, Kozicz T, et al. Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator. Anesthesiology. 2015;122:399–406.
244. Khoromi S, Cui L, Nackers L, Max MB. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain. 2007;130:66–75.
245. Jacobs JH, Grayson MF. Trial of an anti-inflammatory agent (indomethacin) in low back pain with and without radicular involvement. Br Med J. 1968;3:158–160.
246. Goldie I. A clinical trial with indomethacin (Indomee®) in low back pain and sciatica. Acta Orthop Scand. 1968;39:117–128.
247. Kozin F, Ryan LM, Carerra GF, Soin JS, Wortmann RL. The reflex sympathetic dystrophy syndrome (RSDS). III. Scintigraphic studies, further evidence for the therapeutic efficacy of systemic corticosteroids, and proposed diagnostic criteria. Am J Med. 1981;70:23–30.
248. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342:1012–1016.
249. van de Beek WJ, Schwartzman RJ, van Nes SI, Delhaas EM, van Hilten JJ. Diagnostic criteria used in studies of reflex sympathetic dystrophy. Neurology. 2002;58:522–526.
250. Stanton-Hicks M, Jänig W, Hassenbusch S, Haddox JD, Boas R, Wilson P. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain. 1995;63:127–133.
251. Bruehl S, Harden RN, Galer BS, et al. External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain. Pain. 1999;81:147–154.
252. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8:326–331.
253. Harden RN, Bruehl S, Perez RS, et al. Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain. 2010;150:268–274.
254. Benzon HT, Liu SS, Buvanendran A. Evolving definitions and pharmacologic management of complex regional pain syndrome. Anesth Analg. 2016;122:601–604.
255. Sigtermans MJ, van Hilten JJ, Bauer MC, et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009;145:304–311.
256. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147:107–115.
257. Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga V. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis. 1997;56:201–204.
258. Robinson JN, Sandom J, Chapman PT. Efficacy of pamidronate in complex regional pain syndrome type I. Pain Med. 2004;5:276–280.
259. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study. J Rheumatol. 2000;27:1477–1483.
260. Varenna M, Adami S, Rossini M, et al. Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study. Rheumatology (Oxford). 2013;52:534–542.
261. Goebel A, Netal S, Schedel R, Sprotte G. Human pooled immunoglobulin in the treatment of chronic pain syndromes. Pain Med. 2002;3:119–127.
262. Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. 2010;152:152–158.
263. Dirckx M, Groeneweg G, Wesseldijk F, Stronks DL, Huygen FJ. Report of a preliminary discontinued double-blind, randomized, placebo-controlled trial of the anti-TNF-α chimeric monoclonal antibody infliximab in complex regional pain syndrome. Pain Pract. 2013;13:633–640.
264. Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in patients with complex regional pain syndrome: a double-blind placebo-controlled trial of topical ketamine. Pain. 2009;146:18–25.
265. Manicourt DH, Brasseur JP, Boutsen Y, Depreseux G, Devogelaer JP. Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity. Arthritis Rheum. 2004;50:3690–3697.
266. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004;4:13.
267. Groeneweg G, Huygen FJ, Niehof SP, et al. Effect of tadalafil on blood flow, pain, and function in chronic cold complex regional pain syndrome: a randomized controlled trial. BMC Musculoskelet Disord. 2008;9:143.
268. Collins S, Zuurmond WW, de Lange JJ, van Hilten BJ, Perez RS. Intravenous magnesium for complex regional pain syndrome type 1 (CRPS 1) patients: a pilot study. Pain Med. 2009;10:930–940.
269. Fischer SG, Collins S, Boogaard S, Loer SA, Zuurmond WW, Perez RS. Intravenous magnesium for chronic complex regional pain syndrome type 1 (CRPS-1). Pain Med. 2013;14:1388–1399.
270. Perez RS, Pragt E, Geurts J, Zuurmond WW, Patijn J, van Kleef M. Treatment of patients with complex regional pain syndrome type I with mannitol: a prospective, randomized, placebo-controlled, double-blinded study. J Pain. 2008;9:678–686.
271. Breuer AJ, Mainka T, Hansel N, Maier C, Krumova EK. Short-term treatment with parecoxib for complex regional pain syndrome: a randomized, placebo-controlled double-blind trial. Pain Physician. 2014;17:127–137.
272. Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand. 1982;148:653–655.
273. Braus DF, Krauss JK, Strobel J. The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol. 1994;36:728–733.
274. Kalita J, Vajpayee A, Misra UK. Comparison of prednisolone with piroxicam in complex regional pain syndrome following stroke: a randomized controlled trial. QJM. 2006;99:89–95.
275. Barbalinardo S, Loer SA, Goebel A, Perez RS. The treatment of longstanding complex regional pain syndrome with oral steroids. Pain Med. 2016;17:337–343.
276. Serpell MG; Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99:557–566.
277. Sinis N, Birbaumer N, Gustin S, et al. Memantine treatment of complex regional pain syndrome: a preliminary report of six cases. Clin J Pain. 2007;23:237–243.
278. Gustin SM, Schwarz A, Birbaumer N, et al. NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation. Pain. 2010;151:69–76.
279. Gobelet C, Waldburger M, Meier JL. The effect of adding calcitonin to physical treatment on reflex sympathetic dystrophy. Pain. 1992;48:171–175.
280. Bickerstaff DR, Kanis JA. The use of nasal calcitonin in the treatment of post-traumatic algodystrophy. Br J Rheumatol. 1991;30:291–294.
281. Gobelet C, Meier JL, Schaffner W, Bischof-Delaloye A, Gerster JC, Burckhardt P. Calcitonin and reflex sympathetic dystrophy syndrome. Clin Rheumatol. 1986;5:382–388.
282. Sahin F, Yilmaz F, Kotevoglu N, Kuran B. Efficacy of salmon calcitonin in complex regional pain syndrome (type 1) in addition to physical therapy. Clin Rheumatol. 2006;25:143–148.
283. Hamamci N, Dursun E, Ural C, Cakci A. Calcitonin treatment in reflex sympathetic dystrophy: a preliminary study. Br J Clin Pract. 1996;50:373–375.
284. Zuurmond WW, Langendijk PN, Bezemer PD, Brink HE, de Lange JJ, van loenen AC. Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream. Acta Anaesthesiol Scand. 1996;40:364–367.
285. Perez RS, Zuurmond WW, Bezemer PD, et al. The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain. 2003;102:297–307.
286. Safarpour D, Salardini A, Richardson D, Jabbari B. Botulinum toxin A for treatment of allodynia of complex regional pain syndrome: a pilot study. Pain Med. 2010;11:1411–1414.
288. Gereau RWt, Sluka KA, Maixner W, et al. A pain research agenda for the 21st century. J Pain. 2014;15:1203–1214.