Letter to the editor: Precision-guided multi-site insular deep brain stimulation for refractory neuropathic pain.

Background: Peripheral nerve stimulation (PNS) has emerged as a promising treatment for refractory neuropathic pain in the upper extremities, particularly for patients unresponsive to conventional therapies. This systematic review and meta-analysis aims specifically to evaluate the effectiveness and safety of nerve stimulation of the brachial plexus (BP) for managing chronic neuropathic pain in the upper extremities. Methods: A comprehensive literature search was conducted following PRISMA guidelines across major databases, including PubMed, Scopus and Embase. Five studies met the inclusion criteria, encompassing a total of 157 patients with BP or other peripheral nerve injuries. The primary outcome measures included pain reduction and quality of life improvement, assessed through validated pain scales such as the Numerical Rating Scale (NRS) and patient-reported outcomes. Results: This meta-analysis demonstrated significant reductions in pain scores following BP nerve stimulation (MD: -4.88, 95% CI: -5.80 to -3.96, p < 0.05). Additionally, improvements in quality of life were observed, with over 30% enhancement in Short Form (SF)-36 scores. The overall complication rate was low, with only 9.2% of patients experiencing adverse events, such as lead migration or postoperative infection. Conclusions: These findings suggest that PNS at the level of the BP is both a safe and effective intervention for the management of refractory neuropathic pain in the upper extremities. Level of Evidence: Level IV (Therapeutic).

This retrospective review evaluates pain and patient-defined functional goal improvement utilizing bipolar peripheral nerve stimulation (PNS) in chronic neuropathic and nociceptive pain states. Our dataset includes 24 patients who underwent implantation of a permanent peripheral nerve stimulator from January 2018 through December 2022. A total of 29 leads were implanted amongst 24 patients, with 5 patients having leads at 2 different dermatomes. Fifteen leads were placed for primarily neuropathic pain, and 14 leads were placed for nociceptive pain. Inclusion criteria were the following: pain duration greater than 6 months, documented peri-procedural Numerical Pain Rating Scale (NPRS) and greater than 60 days follow-up post implant. Data was collected and analyzed showing that 89.6% of implants at 6 months follow-up and 70% at 12 months follow-up achieved 50% or greater pain relief. A significant reduction in NPRS scores when comparingpre-procedure pain scores (Median = 7, n = 29) to 6-month follow-up data (Median = 2, n = 29), p<0.001 with a large effect size, r =0.61.Ninety-three percent of patients reported achieving their personal functional goal. Twelve of the fourteen (86%) leads implanted for primary nociceptive pain and fourteen of the fifteen (93%) leads implanted for neuropathic pain achieved ≥50% relief at 6 months. At twelve months, seven leads in each group provided ≥50% sustained pain relief. Of the 14 patients that were on opioids, 6 discontinued, while another 2 had a reduction in oral morphine milligram equivalents (MME) at the 12-month follow-up. This retrospective review demonstrates the potential clinical application of PNS in both nociceptive and neuropathic pain states. Further prospective studies are warranted to validate the effectiveness of PNS in the treatment of refractory nociceptive and neuropathic pain states.

Motor cortex stimulation for refractory neuropathic pain. Long-term outcome

The pattern of upper-limb muscle activation following painful stimulation has not been clarified in detail. We investigated the short-term inhibitory and excitatory effects of painful electrical digital stimulation on the motoneuron pools of distal and proximal upper-limb muscles. Transcranial magnetic stimulation (TMS) was used as test stimulus, and painful digital nerve stimulation as conditioning stimulus for motor evoked potential (MEP) recordings over the abductor digiti minimi (ADM), abductor pollicis brevis (APB), biceps brachii (BB), and deltoid muscles. Inhibition of the conditioned MEP response was most prominent in the distal muscles, whereas BB and deltoid muscles were only weakly inhibited. The mean MEP response over APB decreased with painful cutaneous stimuli, showing maximum inhibition (by 82%) at interstimulus intervals (ISIs) of 50 ms. Inhibition in the ADM was maximal (49%) but less pronounced at an ISI of 40 ms. The BB and deltoid muscles showed inhibition by 25% and 29%, respectively. Significant facilitation was present in BB and deltoid muscles by 43% and 41% at an ISI of 100 ms, but not in the smaller hand muscles. The observed pattern of upper-limb muscle activation corresponds to the protective withdrawal reflex and the neuronal basis of the observed short-term modulation of motor activity is compatible with a spinal or brainstem pathway.

Spinal cord stimulation (SCS) offers new hope for patients with neuropathic pain. SCS "neuromodulates" the transmission and response to "painful" stimuli. The efficacy of SCS has been established in the treatment of a variety of neuropathic pain conditions and more recently in refractory angina pectoris, peripheral vascular disease, and failed back surgery syndrome. Recent publications suggest that visceral pain could be successfully treated with SCS. We report the first successful use of a spinal cord stimulator in the treatment of refractory neuropathic mediastinal, esophageal, and anterior neck pain following esophagogastrectomy.

Non-invasive trial testing for trigeminal branch stimulation to treat refractory trigeminal neuropathic pain: A technical note

Objectives:Patients refractory to older therapies for neuropathic pain (NeP) have few remaining therapeutic options. This study evaluates the cost-utility of pregabalin in the treatment of patients with refractory neuropathic pain in Sweden, from a healthcare and a societal perspective.Study limitations:The use of non-randomized (observational) data to determine the effectiveness of treatments for NeP. The use of non-Swedish data for some input parameters in the model.Methods:A previously constructed discrete event simulation model was adapted to compare pregabalin combined with usual care to usual care alone in a Swedish setting. Pain profiles were generated using clinical data from five non-randomized pregabalin studies in refractory NeP patients. Utility data were generated from a UK survey of patients with NeP. Cost data were generated from the Swedish Dental and Pharmaceutical Benefits Board (TLV’s) product price database, a national NeP register, and a regional registry study. Indirect costs were estimated from published sources. One-way and probabilistic sensitivity analyses evaluated uncertainty in the model’s output.Results:The incremental cost-effectiveness ratio (ICER) for pregabalin plus usual care treatment compared to usual care was 51,616 SEK/€5364 and 123,993 SEK/€12,886 with and without indirect costs, respectively. One-way sensitivity analyses confirmed the clinical input data as the main driver of the model; even considerable changes to all other input parameters had only a modest effect on the ICER. The ICER remained well below a conservative threshold of 347,495 SEK /€36,113/£30,000 in all scenarios modelled.Conclusions:This study found pregabalin combined with usual care to be cost-effective compared to usual care in patients with refractory NeP from a Swedish Health Care perspective. Moreover, sensitivity analysis showed pregabalin’s cost-effectiveness to be robust in all scenarios modelled.

Aim: The aim of this case series was to report the use of 8% topical capsaicin patch (marketed under the trade name Qutenza®)a in the management of refractory neuropathic pain (NP) in adult patients with type 1 neurofibromatosis (NF1).Methods: Capsaicin has been suggested for NF1 patients suffering from refractory peripheral NP despite several years of analgesic treatments. The patch was applied for 60 minutes on the painful area, with tolerability control (blood pressure, intensity of pain and dermal reaction). The evaluation was done at the beginning of treatment and during the 2 months following the first treatment (phone calls at weeks 1, 2, 4 and 8). The primary efficacy criterion was the response rate: a patient was considered to be responding if he or she reported an average relief ≥30% at the time of the follow-up calls. The secondary criteria were: interference scores (QCD), Patient Global Impression of Change (PGIC) and overall treatment satisfaction, self-reported by the patient.Results: Eight patients (5 females/3 males, 41.8 ± 8.2 years of age) received a first treatment with capsaicin. Patients had pre-existing pain for 6.6 years (±6.0) and were currently receiving an average of 6.1 (±3.9) different analgesics. The response rate was 37.5%. The three responders felt globally improved and satisfied, with the improvement in overall condition as interference scores decreased. Apart from the expected local reactions, the treatment was not accompanied by systemic side effects.Conclusions: As suggested in this case series, capsaicin provided pain relief in certain NF1 patients with resistant NP. The response rate is that expected in multi-line refractory NP. A significant benefit on the overall condition of some patients was observed. In addition, this topical treatment is administered every 3 months without systemic effects. This study is limited by the small number of patients, but was intended to describe a new and well tolerated alternative treatment.

Although the thalamus is an important module in "pain networks," there are few studies of the effect of experimental pain upon thalamic oscillations. We have now examined the hypothesis that, during a series of painful cutaneous laser stimuli, thalamic signals will show stimulus-related gamma-band spectral activity, which is modulated by attention to vs. distraction from the painful stimulus. When the series of laser stimuli was presented, attention was focused by counting the laser stimuli (count laser task), while distraction was produced by counting backward (count back plus laser task). We have studied the effect of a cutaneous laser on thalamic local field potentials and EEG activity during awake procedures (deep brain stimulation implants) for the treatment of essential tremor. At different delays after the stimulus, three low gamma- (30-50 Hz) and two high gamma-band (70-90 Hz) activations were observed during the two tasks. Greater high-gamma activation was found during the count laser task for the earlier window, while greater high-gamma activation was found during the count back plus laser task for the later window. Thalamic signals were coherent with EEG signals in the beta band, which indicated significant synchrony. Thalamic cross-frequency coupling analysis indicated that the phase of the lower frequency activity (theta to beta) modulated the amplitude of the higher frequency activity (low and high gamma) more strongly during the count laser task than during the count back plus laser task. This modulation might result in multiplexed signals each encoding a different aspect of pain.

A number of antidepressant medications, as well as electroconvulsive therapy, have been shown to reduce chronic pain. Slow-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the right dorsolateral prefrontal cortex has also been shown to have an antidepressant effect. Given the high degree of suffering experienced by subjects with chronic neuropathic pain and the treatment resistance noted in this population, the use of slow-frequency rTMS as adjuvant therapy may be of significant clinical benefit. Fifteen sessions of 1-Hz rTMS (1600 stimulations/session) were applied to the right dorsolateral prefrontal cortex as adjuvant treatment in 9 subjects with refractory neuropathic pain over 3 weeks. Pain and depression ratings were performed at baseline, weekly during rTMS treatment, and monthly for up to 3 months after treatment. Five males and 4 females participated, and all had longstanding refractory neuropathic pain (range, 1-19 years), with an average baseline pain rating of 7.3 and no depression (Hamilton Rating Scale for Depression average, 3.6; range, 0-8). Three subjects had a greater than 50% decline in pain ratings by the completion of rTMS treatments, and 1 subject responded more slowly with greater than 50% improvement in pain by the end of the 3-month follow-up. An improvement in pain ratings was noted in responders within the first week. Although these are preliminary findings in an open treatment trial, the subjects in this trial are among the least likely to have a placebo response. Given that rTMS is a well-tolerated and noninvasive intervention, any sustained improvement in neuropathic pain with rTMS is encouraging.

Magnetic resonance-guided focused ultrasound (MRgFUS) central lateral thalamotomy (CLT) has not yet been validated for treating refractory neuropathic pain (NP). Our aim was to assess the safety and potential efficacy of MRgFUS CLT for refractory NP. In this prospective, nonrandomized, single-arm, investigator-initiated phase I trial, patients with NP for more than 6 months related to phantom limb pain, spinal cord injury, or radiculopathy/radicular injury and who had undergone at least one previous failed intervention were eligible. The main outcomes were safety profile and pain as assessed using the brief pain inventory, the pain disability index, and the numeric rating scale. Medication use and the functional connectivity of the default mode network (DMN) were also assessed. Ten patients were enrolled, with nine achieving successful ablation. There were no serious adverse events and 12 mild/moderate severity events. The mean age was 50.9 years (SD: 12.7), and the mean symptom duration was 12.3 years (SD: 9.7). Among eight patients with a 1-year follow-up, the brief pain inventory decreased from 7.6 (SD: 1.1) to 3.8 (SD: 2.8), with a mean percent decrease of 46.3 (SD: 40.6) (paired t -test, P = .017). The mean pain disability index decreased from 43.0 (SD: 7.5) to 25.8 (SD: 16.8), with a mean percent decrease of 39.3 (SD: 41.6) ( P = .034). Numeric rating scale scores decreased from a mean of 7.2 (SD: 1.8) to 4.0 (SD: 2.8), with a mean percent decrease of 42.8 (SD: 37.8) ( P = .024). Patients with predominantly intermittent pain or with allodynia responded better than patients with continuous pain or without allodynia, respectively. Some patients decreased medication use. Resting-state functional connectivity changes were noted, from disruption of the DMN at baseline to reactivation of connectivity between DMN nodes at 3 months. MRgFUS CLT is feasible and safe for refractory NP and has potential utility in reducing symptoms as measured by validated pain scales.

BackgroundZiconotide and morphine are intrathecal (IT) drugs approved by the FDA and EMA for the treatment of chronic pain. The aim of this study was to determine whether opioid rescue can be achieved by gradually increasing doses of ziconotide, and to establish a practical protocol for its implementation.MethodsFive patients unresponsive to IT morphine due to lack of efficacy or adverse events such as endocrine dysfunction, constipation and tolerance were selected. All had refractory, neuropathic or mixed pain. Ziconotide was gradually introduced while maintaining or reducing morphine doses in proportion to the ziconotide titration. Dose adjustments were made every 2 weeks, with a weekly ziconotide increase of 0.5 μg.ResultsOf the five patients, three were female and two were male, with ages ranging from 53 to 75 years. Two had cancer (one with colon cancer and one with osteosarcoma), two had persistent spinal pain syndrome type 2, and one had spastic paraparesis. After 6 weeks of ziconotide treatment, all individuals showed a substantial reduction in daily morphine dosage (from 10 to 5.5 mg/day), which was associated with improved control of adverse events. Similarly, notable reductions were observed in pain intensity (from 8.0 to 2.5, measured by VAS) and neuropathic symptoms (from 6.0 to 2.0, measured by DN4). The most frequently improved neuropathic symptoms included tingling (4 patients), hypoesthesia to touch (3 patients), and pain evoked by brushing (3 patients). The duration of the rescue protocol ranged from 5 to 11 weeks.ConclusionIntrathecal opioid rescue with ziconotide emerges as a viable therapeutic option for patients with refractory pain and a neuropathic component, or for those who develop adverse events associated with IT morphine. Low doses and slow titration of ziconotide may help minimize adverse events while maintaining analgesic benefit.

Spinal Cord Stimulation and Evidence-Based Medicine—Cui Bono

This appendix addresses lidocaine infusions for refractory neuropathic pain. Lidocaine is an amide local anesthetic that suppresses neuronal discharge via blockade of sodium channels and N-methyl-d-aspartate receptors. Outpatient intravenous lidocaine infusions have been demonstrated to be safe and efficacious in a diverse set of neuropathic and non-neuropathic pain conditions. Many chronic pain patients experience prolonged pain relief lasting an average of 1 to 2 weeks post-infusion, and some experience pain relief up to 4 weeks post-infusion. Unfortunately, there is a paucity of data regarding intravenous lidocaine infusions in the setting of palliative and hospice care. One retrospective, uncontrolled study investigated the use of intravenous lidocaine in 82 opioid-refractory cancer pain patients on a palliative care unit. It was found that a majority of patients had at least a short-term pain response to intravenous lidocaine. Ultimately, a risk–benefit assessment and analysis should be performed for all patients whose neuropathic pain is not adequately controlled with potentially safer and effective, approved pharmacotherapeutic agents.

Cryoneurolysis in Patients with Dorsal Neuropathic Pain Secondary to Tumor Invasion