Amber N. Mitchell, MD

Migraine headache is one of the most prevalent neurologic conditions, but remains pathogenically poorly understood and often suboptimally treated.

One purported pathophysiologic mechanism for this acute disorder is cortical spreading depression, which involves the slow propagation of a depolarization wave in the gray matter of the cerebral cortex.

 The most clinically apparent symptom of this benign phenomenon is the migraine's visual aura of migrating scintillations, representing an excitation-depression wave propagating across the human primary visual cortex.

During the cortical spreading depression, several biochemical changes occur, including perturbations of brain ion homeostasis and aberrant efflux of excitatory amino acids from neurons. Tonabersat is a novel agent aimed at selectively binding and blocking glial cell gap junction activity and thus interfering with excitation of nearby trigeminal neurons and propagation of cortical depolarization.

, 133 studies were identified in the search, and only two randomized, double-blind placebo-controlled clinical trials (RCCTs) met criteria for the analysis. Tonabersat was administered at a dose of 40 mg at the onset of migraine with or without aura. In one of the studies, the medication was given at a pulse dose of 220 mg for two weeks, and then reduced to 40 mg for the rest of the testing period. The primary outcome measure was the change in mean number of migraine headache days of which no statistical difference was found. The secondary outcome measures were the following: change in the nature of migraines, 50% responder rates, reduction in rescue medication administration, and adverse events. There was a clinically-significant difference between treatment and control groups in Hauge’s study, showing a reduction in aura (with or without headache) over the 12-week study period. The 50% responder rate was not clinically significant in the study by Goadsby. Clinical significance likewise was not found for reduction of consumption of rescue medication with the study drug.

Adverse events were mild and included nausea, dizziness, and fatigue, as well as upper respiratory tract and urinary tract infections. Of the 199 patients studied, only one patient dropped out due to adverse events in the tonabersat group.

There was a lack of evidence to support use of tonabersat for migraine prophylaxis. Tonabersat was well-tolerated and long-term prospective trials with higher power may show a benefit from the targeted mechanism of this drug.

Due to the rigor of inclusion criteria, only two RCCTs were included in the systematic review for a total patient trial number of 199 patients. This number represents a low-powered study and suboptimal trial number for a systematic review.

As with most systematic reviews, patient populations analyzed tend to be diverse. The study did attempt to assess for heterogeneity by subgroup analysis. It should be pondered whether the migraineurs included in the study were completely compliant with the medication restrictions of their respective trial. It is possible that they could have been taking other herbal or allopathic agents not otherwise mentioned which may have modified the outcomes of the study.

If there was a preponderance of occult migraine treatment in the placebo group, then the study would be prone to a type 2 statistical error. In other words, the study would fail to find a difference between groups when a difference truly exists with a favorable effect demonstrated in the tonabersat group. This particular sort of false-negative error could be clarified by a future prospective parallel group study that analyzed two cohorts of tonabersat-treated and placebo, which could be restricted from alternative prophylactic migraine agents during the course of the study so as to obviate confounding variables.

Of note, the study by Goadsby et al had a high attrition rate, including 33 patients who left for no identified cause. Data for the reasons for attrition may be useful to identify occult adverse effects of the medication. Therefore, this study is prone to attrition bias.

Also, in each trial, the effect of tonabersat was studied for only three months at a dose of 40 mg for the majority of the study period. The reported effective and safe dose range for tonabersat as reported from prior trials is 15 to 80 mg.

 Also, a longer treatment period would offer useful information about delayed therapeutic effects or adverse effects of Tonabersat. Thus, a longitudinal study undertaken for a longer period of time, such as six to 12 months and stratification of cohorts to include patients treated at 40 mg and 80 mg, may clarify if these modifications affect outcomes of efficacy.

In addition, comparison of tonabersat with a gold-standard migraine prophylactic agent or in combination with other prophylaxes would be clinically useful for cohorts of migraineurs with severe disease.

Amber N. Mitchell, MD, is a neurology resident at Albany Medical Center Hospital.

1. Cao Y, Zheng OJ. Tonabersat for Migraine Prophylaxis: A systematic review. 

2. Lauritzen M, Dreier JP, Strong AS. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. 

3. Damodaram S, Thalakoti S, Freeman SE, Garrett FG, Durham PL. Tonabersat inhibits trigeminal ganglion neuronal-satellite glial cell signaling. 

4. Silberstein SD. Tonabersat, a novel gap-junction modulator for the prevention of migraine. 

Articles

A recent review found that tonabersat, a novel benzoylamino benzopyran compound, is well-tolerated, but no better than placebo for migraine prophylaxis. 

Evaluating the Effectiveness of Tonabersat for Migraine Prophylaxis

Epidural motor cortex stimulation (MCS) is an alternative, adjuvant treatment for intractable neuropathic central pain. MCS consists of invasive implantation of a device epidurally with continuous stimulation at frequencies that serve to supplement conventional pharmacologic analgesics. Prior studies have shown that positive analgesic response to noninvasive repetitive transcranial magnetic stimulation (rTMS) serves as an adequate preoperative predictor of continuous MCS efficacy. 

 Therefore, an analgesic effect of noninvasive rTMS often serves as an aid to identify candidates for invasive epidural implantation of the MCS apparatus. However, some studies have shown that a poor rTMS response may fail to identify some successful responders to subsequent MCS.

With this in mind, the authors of “Is Life Better after Motor Cortex Stimulation for Pain Control? Results at Long-Term and their Prediction by Preoperative rTMS,” published in 

, sought to clarify the predictive value of rTMS with respect to MCS and to assess long-term pain reduction and quality of life scores in a blinded fashion.

For the study, 20 patients (mean age 54.3 years, 45% female), were randomized to two cohorts of sham vs. active 20Hz-rTMS in a cross-over model, before all patientswere submitted to MCS surgery. There was a statistically significant pain reduction of 14.6% for active rTMS versus 2.9% for the sham group. Effects of MCS at six months and six years were included. Fifty percent of patients retained long-term benefit of MCS by both intensity and quality of life assessments (ability to function free of pain and dependence).

The results of this study showed that MCS was beneficial regardless of previous response to non-invasive preliminary rTMS, although positive response to a single session of rTMS by combined pain assessment and henceforth long-term response to continuous MCS had a 90% positive predictive value (PPV) and 67% negative predictive value at long-term assessments.

Transcranial magnetic stimulation was independently efficacious (14.6% vs. 2.9% pain reduction for sham) outside of response to MCS at 6 months and mean 6 years (37% and 28%, respectively). However, those who did experience analgesic effect from rTMS were more likely to benefit from MCS with a 90% PPV.

In this study, assessments of pain improvement were undertaken by blinded physicians, who were naïve to a patient’s cohort designation. Blinded assessments were not done in prior studies with motor cortex stimulation, which may have introduced a form of operator bias into final subjective assessments about pain control. Thus, by the sound methodology of blinded review of a patient’s analgesic response, this study was immune to this form of bias.

The short-term and long-term assessments of pain control and quality of life were included in the longitudinal analysis of transcranial and intracranial stimulation. Though beneficial to survey patients several years after implantation to deduce longevity of analgesia, there would have been some merit to evaluating patients at shorter intervals, such as yearly or every two years to assess the average time to peak efficacy.

The use of both qualitative and quantitative measures of pain relief has more global and clinically-relevant merit than prior studies, which relied on pain score measures. Long-term MCS results on the HowRu questionnaire showed that modulation of anxiety, depression, and vocational/avocational disability measures lagged beyond the noted improvement in physical pain and autonomy. This may be due to recall bias and underestimation of the absolute pain improvement and functioning from a remote point in time.

In addition, the long-term assessment of pain relief carried out over 2-9 years provides a solid basis to determine if pain relief afforded by epidural motor cortex stimulation is fleeting or enduring. Quality of life assessments should be included in future longitudinal studies.

Only 20 patients were studied, and the power of the study is limited. The patient population was not homogeneous, with patients presenting with diverse etiologies of medically refractory neuropathic pain, from central post-stroke pain to trigeminal neuralgia to peripheral brachial plexopathy.

Only three patients experienced interval improvement in pain scores from the 6 months to the mean 6 years assessments. This again may reflect intrinsic differences of this population (concurrent pharmacologic use, central pain etiology more amenable to MCS, concurrent neuroses/psychoses). It would be interesting to explore the neurophysiologic basis of the procedure and explore whether certain pain pathways are more responsive to this modality. For now, this surgical option remains one of adjuvant utility to gold standards of pain management.

Of course, the study was conducted at only one medical center and external validity was reduced, but these results certainly may guide neurologists and neurosurgeons to conduct future higher-powered studies beyond this pilot study, which nevertheless, provides predictive outcomes of this innovative procedure for intractable neuropathic pain.

1. Andre-Obadia N, Mertens P, Lelekov-Boissard T, et al. Is Life Better After Motor Cortex Stimulation for Pain Control? Results at Long-Term and their Prediction by Preoperative rTMS. 

2. Migita K, Uozumi T, Arita K, Monden S. Transcranial magnetic coil stimulation of motor cortex in patients with central pain. 

 1995; 36:1037-1039; discussion 1039-1040.

3. Canavero S, Bonicalzi V, Dotta M, et al. Transcranial magnetic cortical stimulation relieves central pain. 

4. Lefaucheur JP, Menard-Lefaucheur I, Goujon C, et al. Predictive values of rTMS in the identification of responders to epidural motor cortex stimulation therapy for pain. 

Patients who also responded positively to preoperative non-invasive transcranial stimulation analgesic effect were more likely to experience long-term benefit from MCS.

Motor Cortex Stimulation Provides Long-Term Analgesia for Neuropathic Pain 

Chronic nonspecific low back pain (CNLBP) secondary to nonspecific musculoskeletal inflammation of three months or more duration is one of the leading causes of activity limitation, impaired quality of life, and occupational truancy.

 Pharmacologic intervention remains an essential part of the treatment paradigm (at least in the short-term), in addition to physical therapy and exercise. Though the female gender and middle to elderly-aged individuals are more commonly affected, the global mean point prevalence of activity-limiting low back pain endured more than one day was estimated to be 11.9%, and the global mean lifetime prevalence of low back pain is 38.9%,

 with North American estimates as high as 85%.

The authors of “Drug Therapy for the Treatment of Chronic Nonspecific Low Back Pain: Systematic Review and Meta-analysis,” published in

, conducted a systematic review and meta-analysis of randomized controlled trials from 2002 to 2012 that assessed oral and injection drug therapy for chronic nonspecific low back pain in adults (18 years and older). Of the 23 trials analyzed, there was a trend of use of cyclo-oxygenase-2 (COX-2) nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, and opioids in this patient population. Antiepileptics and antidepressants were studied less commonly and mainly used in adjuvant roles.

Use of COX-2 NSAIDs resulted in the greatest margin of pain relief, with a standardized mean difference (SMD) of -12.03 (95% confidence interval [-15 to -9.06]). This was followed by opioids, with a SMD of -5.18 (95% CI of -8.3 to -2.05), and partial opioid agonists such as buprenorphine, with a SMD of -7.46 (95% CI of -11.87 to -3.04). Opioids were likewise more effective than placebo for global functional improvement.

Though statistically insignificant for pain relief, tramadol demonstrated improved functional status using the fixed-effect model of global improvement, with weighted mean difference of -0.24. Analysis of the individual opioid oxycodone showed a similar trend of statistical insignificance for pain relief, but patients who received treatment with the drug demonstrated significant global improvement. Oxymorphone was statistically significant for both pain relief and global improvement. Data from a few pooled studies demonstrated improved pain relief indices for topiramate, duloxetine, and bupropion, suggesting a limited role for antiepileptics and antidepressants for CNLBP. Interestingly, there was no statistically significant efficacy difference found between traditional NSAIDs and COX-2 NSAIDs, but COX-2 NSAIDs showed fewer side effects after statistically pooling data from two studies.

This systematic review of the pharmacologic treatment of chronic low back pain was comprehensive for analysis of oral agents, identification of biases, and demonstration of study heterogeneity or homogeneity. The heterogeneity of patient populations studied is inevitable when the primary disease (chronic low back pain) is broad and inclusive of a spectrum of underlying etiologies.

Although statistical pooling was enabled by statistical models for clinical heterogeneity in this study, the qualitative criteria used were flawed in that it specified CNLBP as lower back pain with or without radiation. Radicular back pain is a feature of neurogenic back pain—a subdivision which was semantically excluded from the study analysis of nonspecific back pain. The treatment effects may be skewed by inclusion of neurogenic back pain patients in this group, and perhaps tramadol is shown to be more effective than if this subgroup were excluded, thus inflating global improvement measures.

One of the inescapable flaws of any meta-analysis is the intrusion of methodological variation. For example, what defines chronic non-specific low back pain?  Low back pain may be the phenotype of myriad causes, including but not limited to: musculoskeletal strain, degenerative disc disease, disc herniation, spinal stenosis, osteoporosis, trauma, and vertebral compression fracture or combination thereof. Certain etiologies such as disc herniation and lumbar muscle strain may respond more favorably to NSAIDs by dint of their inflammatory mechanisms. Rarer outlier etiologies, such as ankylosing spondylitis, osteomyelitis, and metastatic or primary tumors, may be more responsive to local site injection or focused pharmaco-surgical interventions.

As a result of studying the entity of chronic low back pain, treatment effects may show dramatic variations across different studies. To minimize this effect in the meta-analysis, chronic nonspecific low back pain excluded causes such as: metastatic disease, inflammation, and infection, as well as exceptional cohorts of pregnant women and cases symptomatic of mechanical injury. An alternative means of eliminating the outlier effect of a heterogeneous cohort would be to prospectively compare two drugs in one particular etiology of back pain that is objectively proven, such as spinal stenosis or anterolisthesis. However, such a study would suffer from the shortcoming of reduced number of subjects and reduced power to study the effect of the therapeutic intervention, which can be more easily demonstrated in a systematic review.Gender stratification would be interesting as well, since studies have shown a greater percentage of female CNLBP sufferers.Sampling error may also be at play as some providers may favor administration of one class of drugs over another, prescribing one agent to everyone and thus improving the probability of success and under-prescribing another agent, including using it in situations in which it is doomed to fail. A side-by-side comparative study of NSAIDs versus opioids would provide useful prospective data of CNSLBP.

In addition, special considerations of combination therapy were not addressed by this analysis. Controlling for concomitant administrations of NSAIDs, opioids, tramadol, antiepileptics, and antidepressants was not addressed, and thus, the reported effect of individual agents may be confounded.

Although effective use of adjuvant epidural corticosteroids and facet-joint and trigger point injections of local anesthetics (bupivacaine, sarapin) for chronic low back pain has been demonstrated,

 injection drug therapy was not mentioned in this review. Due to significant methodological heterogeneity noted at times amongst the included studies, single summary measures, such as mean prevalence of pain relief, should be interpreted with caution and with consideration of the specific characteristics of the prospective patient being treated. For example, a patient with chronic low back pain and stage III chronic renal disease may not be the optimum candidate for NSAID therapy despite their demonstration of superiority in this systematic review, and local epidural steroid injections with fewer systemic adverse effects may be the best individualized treatment option.

Overall, the study demonstrated how the prescient and short-term use of NSAIDs and opioids with pharmacological sensitivity to an individual’s comorbidities may result in pain relief, improved functioning, and reduced vocational and avocational absenteeism.

1. Chung JW, Zeng Y, Wong TK. Drug Therapy for the Treatment of Chronic Nonspecific Low Back Pain: Systematic Review and Meta-analysis.

2. Hoy D, Bain C, Williams G, et al. A systematic review of the global prevalence of low back pain. 

3. White AP, Arnold PM, Norvell DC, et al. Pharmacologic management of chronic low back pain: Synthesis of the evidence. 

4. Tonkovich-Quaranta LA, Winkler SR. Use of Epidural Corticosteroids in Low Back Pain. 

5. Staal JB, de Bie R, de Vet HC. Injection therapy for subacute and chronic low back pain. 

6. Bannwarth B, Kostine M, Shipley E. Nonspecific low back pain: Assessment of available medications. 

According to a recent systematic review, the prescient and short-term use of NSAIDs and opioids with pharmacological sensitivity to an individual's comorbidities may result in pain relief, improved functioning, and reduced vocational and avocational absenteeism.

Are COX-2 NSAIDs the Most Efficacious Treatment for Chronic Nonspecific Low Back Pain?

Painful diabetic neuropathy (PDN) affects the small nerve fibers and is characterized by the sensations of uncomfortable burning, numbness, tingling, warmth, cold, or electric-shock, as well as exaggerated painful sensations to painful stimuli (hyperalgesia) and perception of pain to non-painful stimuli (allodynia).

 This form of neuropathy typically occurs in a length-dependent or stocking-glove distribution affecting the distal legs and arms, and diabetes is the most common etiology.

 According to “Comparative Efficacy and Safety of Six Antidepressants and Anticonvulsants in Painful Diabetic Neuropathy: A Network Meta-analysis,” published in 

 by Rudroju et al, painful diabetic neuropathy remains one of the most unreported (12.5%) and untreated (39.3%) ailments. Given that the astounding prevalence of painful diabetic neuropathy is 10-20% of those suffering from diabetes (prevalence of diabetes in the USA is 25.8 million, or 8.3% of the population, according to the CDC), more than five million Americans are experiencing PDN.

In this network (multiple treatment) meta-analysis and benefit-risk analysis, Rudroju et al compared various antidepressants and anticonvulsants head-to-head with one another or with placebo to rank their safety and efficacy in the management of PDN. After reviewing the literature from 1980 to 2012, the authors identified several randomized controlled studies of both the open-labeled and blinded type for inclusion in the systemic review. They analyzed data for patients age 18 years and older who were exclusively diagnosed with PDN and not combined forms of neuropathy (ie, with post-herpetic neuralgia). The primary outcome measure of efficacy was pain reduction by greater than or equal to 50% using ordinal descriptive scales of improvement. The primary outcome measure of safety was the number of patient withdrawals due to adverse events.

Statistical analysis was conducted in this network meta-analysis using intention-to-treat analysis in a Bayesian model using Markov chain Monte Carlo methods. For the study, the authors labeled efficacy and safety differences between active treatment and another treatment or compared with placebo as statistically-significant when the lower limit of 95% confidence intervals of the odds ratio was greater than one. They performed benefit-risk analysis, with the number of patients with 50% reduction in pain as criteria for benefit and number of withdrawals as standard risk.

After these methods were undertaken, 21 randomized control trials were included in the meta-analysis comparing six active treatments (monotherapy or dual therapy) in a total of 4,219 study participants. Compared with placebo, duloxetine, gabapentin, pregabalin, and venlafaxine exhibited PDN treatment superiority with odds ratios (OR) of 95% confidence intervals (CI) that exceeded 1. However, there was no difference when these active treatments were compared head-to-head. The most efficacious agent was found to be gabapentin followed by venlafaxine, pregabalin, duloxetine/gabapentin, duloxetine, amitriptyline, and placebo. Compared with placebo, the number of withdrawals due to adverse events was higher for amitriptyline, duloxetine, duloxetine/gabapentin, and pregabalin with OR that exceeded 1. The rank order of safety starting with safest was placebo, gabapentin, pregabalin, venlafaxine, duloxetine/gabapentin, duloxetine, and amitriptyline. The final rank order of benefit-risk analysis was as follows: gabapentin, venlafaxine, pregabalin, duloxetine/gabapentin, placebo, duloxetine, and amitriptyline.

Though all 21 studies included in this network meta-analysis were “randomized-controlled trials,” five studies were not placebo-controlled trials, which brings into question the true effect of either medication in this head-to-head trial without a control for comparison. The inclusion of open-label studies in the data may have confounded the results. Having foreknowledge of combination regimens may bias the subjects and investigators into expecting superior outcomes compared with monotherapy or placebo. Also, one may argue that despite the rigor of meta-analysis, patients are not actually being compared head-to-head given the diversity of study locations and actual study conditions (investigators, etc).

Another factor to consider (and not mentioned in the article) is the possibility of polypharmacy in the form of other anticonvulsants and antidepressants used by study participants and unknown to the investigators, which may have modulated outcomes. For example, it was not mentioned whether other pharmaceuticals, such as topical capsaicin creams, topical lidocaine patches, or other alternative medicines used for depression, such as St. John’s Wort, were used concomitantly in these studies.

Interestingly, duloxetine (a serotonin and norepinephrine dual reuptake inhibitor) and pregabalin are FDA-approved for peripheral diabetic neuropathy, though the data from this meta-analysis underscores the unfavorable benefit-risk balance for these agents compared with gabapentin and venlafaxine, also a serotonin-norepinephrine reuptake inhibitor.

 In addition, though the combination of duloxetine and gabapentin proved unfavorable in this analysis, other studies of small fiber neuropathy have shown that combination dual therapy can be beneficial when monotherapy fails.

 There is Level A evidence for combination therapy of tricyclic antidepressants (TCA) with gabapentin and gabapentin with opioids for treatment of diabetic neuropathy and post-herpetic neuralgia.

 Three class I studies showed a greater analgesic effect of the gabapentin/opioids (morphine, oxycodone) and gabapentin/nortriptyline combinations compared to each drug alone in patients with diabetic small fiber neuropathy. The combination of gabapentin and venlafaxine has also been shown to be more effective than gabapentin alone.

 Future prospective studies should be undertaken to evaluate the benefit-risk balance of combination trials for PDN.

Valproate was excluded from the analysis. Given its mechanism of action, valproate may actually serve as an efficacious agent for PDN in selected patients who may benefit from its concomitant anticonvulsant and mood-stabilizing effects. Otherwise, this study does not support its first-line use for isolated PDN.

A flaw of the analysis was the overall short duration of the trial (mean of 10.8 weeks). Diabetic neuropathy is a chronic condition that may evolve and progress over time depending on glycemic control. As such, an individual patient’s clinical symptomatology may be dynamic over time, something that could be best captured by evaluating treatment effect over six months or longer. There was also weak power of the trial with a mean sample size of 82.7 patients per group. Due to the dearth of longitudinal data and low power of the study, the validity of the study is reduced despite its methodological rigor and demonstration of statistical significance.

Amber N. Mitchell is a neurology resident at Albany Medical Center Hospital. 

1. Rudroju N, Bansal D, Talakokkula S, et al. Comparative Efficacy and Safety of Six Antidepressants and Anticonvulsants in Painful Diabetic Neuropathy: A Network Meta-analysis. 

2. McArthur JC. Painful Small Fiber Neuropathies. 

 (Minneapolis, Minn.). 2012 Feb; 18(1):106-25.

3. Tavee J, Zhou L. Small Fiber Neuropathy: A Burning Problem. 

4. The Facts About Diabetes: A Leading Cause of Death in the U.S. 

5. Attal N, Cruccu G, Haanpää M, et al. EFNS Task Force. EFNS Guidelines On Pharmacological Treatment of Neuropathic Pain. 

. 2006 Nov; 13(11):1153—1169. (class I SR).

6. Gilron I, Baley JM, Tu D, et al. Nortriptyline and Gabapentin, Alone and in Combination for Neuropathic Pain: A Double-Blind, Randomised Controlled Crossover Trial. 

7. Hanna M, O’Brien C, Wilson MC. Prolonged-release Oxycodone Enhances The Effects of Existing Gabapentin Therapy in Painful Diabetic Neuropathy Patients. 

8. Simpson DA. Gabapentin and Venlafaxine for the Treatment of Painful Diabetic Neuropathy. 

Meta-analysis of clinical trial data on the use of antidepressants and anticonvulsants for the treatment of painful diabetic neuropathy indicates gabapentin is the most efficacious agent for this condition, while the side effects associated with amitriptyline make it the least tolerable treatment option evaluated in the study. 

Author | Amber N. Mitchell, MD

Articles

Evaluating the Effectiveness of Tonabersat for Migraine Prophylaxis

Motor Cortex Stimulation Provides Long-Term Analgesia for Neuropathic Pain

Are COX-2 NSAIDs the Most Efficacious Treatment for Chronic Nonspecific Low Back Pain?

Evaluating Treatments for Painful Diabetic Neuropathy