Gastón Schechtmann

Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy

Abstract The mechanisms underlying the pain relieving effect of spinal cord stimulation (SCS) on neuropathic pain remain unclear. We have previously demonstrated that suppression of tactile hypersensitivity produced by SCS may be potentiated by i.t. clonidine in a rat model of mononeuropathy. Since the analgesic effect of this drug is mediated mainly via cholinergic mechanisms, a study exploring the possible involvement of the spinal cholinergic system in SCS was undertaken. The effect of SCS was assessed with von Frey filaments in rats displaying tactile hypersensitivity after partial ligation of the sciatic nerve and both SCS‐responding and non‐responding as well as normal rats were subjected to microdialysis in the dorsal horn. Acetylcholine (ACh) was analyzed with HPLC before, during and after SCS. SCS produced significantly increased release of ACh in the dorsal horn in rats responding to SCS whereas the release was unaffected in the non‐responding animals. Furthermore, the basal release of ACh was significantly lower in nerve lesioned than in normal rats. In another group of rats it was found that the response to SCS was completely eliminated by i.t. atropine and a muscarinic M4 receptor antagonist while a partial attenuation was produced by M1 and M2 antagonists. Blocking of nicotinic receptors did not influence the SCS effect. In conclusion, the attenuating effect of SCS on pain related behavior is associated with the activation of the cholinergic system in the dorsal horn and mediated via muscarinic receptors, particularly M4, while nicotinic receptors appear not to be involved.

Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy

Spinal cord stimulation (SCS) is an effective tool in alleviating neuropathic pain. However, a number of well‐selected patients fail to obtain satisfactory pain relief. Previous studies have demonstrated that i.t. baclofen and/or adenosine can enhance the SCS effect, but this combined therapy has been shown to be useful in less than half of the cases and more effective substances are therefore needed. The aim of this experimental study in rats was to examine whether gabapentin or pregabalin attenuates tactile allodynia following partial sciatic nerve injury and whether subeffective doses of these drugs can potentiate the effects of SCS in rats which do not respond to SCS. Mononeuropathy was produced by a photochemically induced ischaemic lesion of the sciatic nerve. Tactile withdrawal thresholds were assessed with von Frey filaments. Effects of increasing doses of gabapentin and pregabalin (i.t. and i.v.) on the withdrawal thresholds were analysed. These drugs were found to reduce tactile allodynia in a dose‐dependent manner. In SCS non‐responding rats, i.e. where stimulation per se failed to suppress allodynia, a combination of SCS and subeffective doses of the drugs markedly attenuated allodynia. In subsequent acute experiments, extracellular recordings from wide dynamic range neurones in the dorsal horn showed prominent hyperexcitability. The combination of SCS and gabapentin, at the same subeffective dose, clearly enhanced suppression of this hyperexcitability. In conclusion, electrical therapy and pharmacological therapy in neuropathic pain can, when they are inefficient individually, become effective when combined.

Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders

Background For patients with psychiatric illnesses remaining refractory to ‘standard’ therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered ‘established’ in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patients capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-up evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.

Baclofen-enhanced spinal cord stimulation and intrathecal baclofen alone for neuropathic pain: Long-term outcome of a pilot study.

In a previously published pilot study, we addressed the possibility to increase the effectiveness of spinal cord stimulation (SCS) applied for neuropathic pain by using adjunct pharmacological therapy. This combined treatment approach was a direct spin‐off from animal experiments aiming at the exploration of transmitter and receptor mechanisms involved in the pain relieving effect of SCS. Out of 48 patients with neuropathic pain of peripheral origin responding poorly to SCS, seven received pumps for intrathecal baclofen (GABA‐B receptor agonist) delivery together with SCS, and four had pumps alone. In order to assess the long‐term effect a follow‐up has been performed, with an average, total treatment time of 67 months. At the follow‐up the remaining nine patients still enjoy about the same pain relief as initially, but with a mean, further dose increase of about 30%. This study demonstrates that a deficient SCS effect in neuropathic pain may be considerably improved by intrathecal baclofen administration, and that this enhanced effect persists for a long‐time. On‐going and future animal studies may provide new and even more efficient pharmaceutical candidates for such combined therapy.

Intrathecal Clonidine Potentiates Suppression of Tactile Hypersensitivity by Spinal Cord Stimulation in a Model of Neuropathy

Spinal cord stimulation (SCS) may provide pain relief in approximately 60%–70% of well selected patients with pain caused by peripheral nerve injury. We have previously demonstrated that intrathecal (IT) administration of small doses of certain drugs, both in experimental animals and in patients, significantly enhances the pain-relieving effect of SCS. The &agr;2-adrenoceptor agonist, clonidine, is extensively used as an adjunct to spinal morphine and is suggested to be particularly effective for neuropathic pain, but its clinical use is limited by side effects such as sedation and hypotension. In this study, we investigated the dose-response characteristics of IT clonidine, and whether a subeffective dose of clonidine could enhance the effect of SCS in nerve-injured rats with tactile hypersensitivity (allodynia). Results showed that clonidine, in doses of 1–20 μg, reduced the hypersensitivity in a dose-dependent manner. In rats in which SCS per se failed to suppress tactile hypersensitivity, the combination of SCS and a subeffective dose of clonidine appeared to be highly synergistic and markedly attenuated the hypersensitivity. These results suggest that small doses of IT clonidine may be combined with SCS in neuropathic pain patients who do not obtain satisfactory relief with SCS alone.

Intrathecal clonidine and baclofen enhance the pain-relieving effect of spinal cord stimulation: a comparative placebo-controlled, randomized trial.

OBJECTIVESpinal cord stimulation (SCS) is a well-established treatment for neuropathic pain; nevertheless, 40% of patients fail to obtain satisfactory pain relief and in many patients, the effect tends to diminish with time. Based on animal experiments, intrathecal baclofen was previously introduced clinically to enhance suboptimal SCS effects. Later animal experiments demonstrated similar data for clonidine. The aim of this study was to elucidate whether intrathecal clonidine or baclofen enhances the effect of SCS in neuropathic pain patients in whom the pain relieving-effect of SCS is inadequate. METHODSA randomized, double-blind, placebo-controlled clinical trial was conducted with 10 patients experiencing neuropathic pain with insufficient pain relief with SCS alone. Clonidine, baclofen, and saline (control) were intrathecally administered by bolus injections in combination with SCS. RESULTSSeven of 10 patients reported significant pain reduction when SCS was combined with active drugs. The mean visual analog scale ratings were reduced by more than 50% with either drug combined with SCS. Four patients previously treated with SCS alone later underwent implantation of a pump for long-term administration of clonidine or baclofen. In the 2 patients with clonidine pumps with a mean follow-up of 15 months, the combined therapy produced pain reduction of 55% and 45%, respectively. The corresponding effect with baclofen was 32% and 82%, respectively, at 7 months follow-up. CONCLUSIONA trial with clonidine and baclofen combined with SCS may be warranted in patients who do not obtain satisfactory pain relief with SCS alone or experienced a decreasing therapeutic effect.

Factors That Influence Outcome of Percutaneous Balloon Compression in the Treatment of Trigeminal Neuralgia

BACKGROUND:Percutaneous balloon compression is an effective, low-cost, simple therapeutic modality with the special advantage of being the only percutaneous technique that can be simply performed with the patient under general anesthesia for the treatment of trigeminal neuralgia. OBJECTIVE:To identify surgical and individual parameters that could influence outcome in patients with trigeminal neuralgia treated with percutaneous balloon compression. METHODS:Within a 5-year period, 66 consecutive percutaneous balloon compressions were performed in 47 patients. The medical and surgical records of all patients were retrospectively reviewed and analyzed for a possible correlation between the following parameters and outcome: balloon shape, balloon volume, compression time, age, sex, type of pain, duration of disease, previous procedures, and trigeminal division affected. Univariate and multivariate analyses were used to test for statistical significance. RESULTS:The initial success rate was 85%, and 36% of the responders are still pain free with a mean follow-up of approximately 20 months, whereas in 33 patients, trigeminal pain recurred after a mean of approximately 17 months. Of the investigated parameters, significant correlations were obtained between balloon shape and all aspects of outcome, previous operations and complication rate, pain type and complication rate, and compression time and postoperative numbness. CONCLUSION:The balloon shape is a parameter with a very strong impact on outcome, and balloon volume should be adjusted to this parameter. Persistent elliptical balloon shapes should raise consideration of aborting the procedure. There were no differences in outcomes between 60 seconds and longer compression times. The number of previous operations did not correlate with pain relief, but seemed to increase the risk of complications. Patients with multiple sclerosis seemed to obtain similar benefit from the procedure as do patients with classic trigeminal neuralgia.

Subthalamic Stimulation for Essential Tremor

Background/Aims/Methods: In order to explore the usefulness and long-term result of subthalamic nucleus (STN) stimulation for the treatment of essential tremor (ET), we evaluated 3 groups of patients undergoing deep brain stimulation (DBS) for ET. Results: Group 1 consisted of 3 patients who 9 years ago at intra-operative testing had good tremor reduction from STN stimulation. The second group consisted of 10 patients treated with DBS in the ventral intermediate (Vim) nucleus of the thalamus. The third group comprised 9 patients subjected to STN stimulation for ET with 1–3 years of follow-up. The 3 ET patients with STN stimulation in group 1 have continued to have excellent tremor reduction for up to 9 years. The second group, with Vim stimulation, showed less favourable long-term results. All of the recent STN stimulation group experienced good tremor reduction, but some of the patients above 70 years of age reported troublesome side effects. Conclusion: Provided that intra-operative test stimulation produces satisfactory tremor control, STN is a good target for long-term treatment of ET. For patients above the age of 70 years, however, the Vim is a preferable target.

Drug-enhanced spinal stimulation for pain: a new strategy

Neuropathic pain is notoriously difficult to manage and only a few classes of drugs may provide adequate benefits. Thus, in many cases spinal cord stimulation (SCS) is considered; however, in this group of patients, between 30-50% of the cases offered a percutaneous SCS trial may fail to obtain a satisfactory effect. Additionally, a certain number of patients with a good initial effect, report that after a period the benefits are reduced necessitating additional peroral drug therapy. Based on animal studies of transmitters and receptors involved in the effects of SCS in neuropathic pain, the GABA-B receptor seems to play a pivotal role for the effect and, moreover, the agonist baclofen injected intrathecally in rats potentiated the SCS effect in animals not responsive to SCS per se. Based on these and further studies, 48 patients with neuropathic pain and inadequate response to SCS were given intrathecal (i.t.) baclofen (ITB) in bolus doses as an adjuvant. In this group 7 patients enjoyed such a good effect that they were implanted with both SCS and drug delivery systems for ITB. Four additional cases received baclofen pumps alone. Some other patients were given intrathecal (i.t.) adenosine in combination with SCS and initially preferred this to baclofen. The chronic use of this drug in a pump however proved to be technically problematic and all the adenosine cases were eventually terminated. At follow-ups, in average 32 and 67 months after start of SCS + baclofen therapy, more than 50% still enjoy a very good effect. The daily dose of baclofen needed to maintain the effects was approximately doubled during the observation period. There were few and mild side-effects. However, in a group of three patients with peroral baclofen therapy and SCS, complaints of side-effects were common and this therapy was terminated. Informal reports from collegues support the negative experience with additional peroral baclofen. In conclusion, in patients with neuropathic pain demonstrating inadequate response to SCS (small VAS reduction; short duration) a trial of intrathecal baclofen in combination with SCS may be warranted.

Subthalamotomy in the treatment of Parkinson's disease: clinical aspects and mechanisms of action

Parkinsons disease (PD) is a neurodegenerative condition that can be pharmacologically treated with levodopa. However, important motor and nonmotor symptoms appear with its long-term use. The subthalamic nucleus (STN) is known to be involved in the pathophysiology of PD and to contribute to levodopa-induced complications. Surgery is considered in patients who have advanced PD that is refractory to pharmacotherapy and who display disabling dyskinesia. Deep brain stimulation of the STN is currently the main surgical procedure for PD, but lesioning is still performed. This review covers the clinical aspects and complications of subthalamotomy as one of the lesion-based options for PD patients with levodopa-induced dyskinesias. Moreover, the authors discuss the possible effects of subthalamic lesioning.