The Effect of Once-Daily Gabapentin Extended Release Formulation in Patients With Postamputation Pain.

OBJECTIVES: To compare gabapentin extended-release, a gastro-retentive formulation, in relieving postamputation pain among gabapentin-experienced and gabapentin-naïve patients. DESIGN: Open-labeled pilot study. SUBJECTS: Sixteen patients with postamputation pain (8 patients in the gabapentin-experienced and 8 patients in the gabapentin-naïve groups). METHODS: Patients were started on gabapentin extended-release and were followed up for 8 weeks. Patients reported their pain severity during rest and movement using a numeric rating scale (NRS), interference of pain with daily activities using the modified brief pain inventory (MBPI) questionnaire, and treatment satisfaction using the treatment satisfaction questionnaire for medication (TSQM). RESULTS: Patients from both gabapentin-experienced and gabapentin-naïve groups achieved a significant and sustainable pain relief over the course of therapy. The pain scores at rest decreased in both gabapentin-experienced and gabapentin-naïve groups from 5.88 ± 1.36 and 4.88 ± 2.95 to 1.88 ± 0.99 and 1.38 ± 1.51, respectively. An average percent of pain relief with gabapentin extended-release was noted to be significant (p < 0.01) after 8 weeks of therapy among gabapentin-experienced (81.25 ± 16.42%) and gabapentin-naïve groups (85 ± 17.73%) when compared to baseline for gabapentin-experienced (31.25 ± 29%) and gabapentin-naïve groups (36.25 ± 34.2%), respectively. Gabapentin-experienced and gabapentin-naïve groups had no significant difference in global satisfaction from treatment (79.14 ± 10.47 and 83.3 ± 20.82), convenience of treatment (73.78 ± 19.04 and 90.44 ± 11.66), effectiveness of treatment (72.6 ± 10.1 and 79.73 ± 11.6). The only statistically significant difference among gabapentin-experienced and gabapentin-naïve groups was found in adverse event tolerability (65.78 ± 10.36 and 85.8 ± 10.14, p < 0.01). CONCLUSION: Once-daily dosing of gabapentin-extended release showed significant improvement in pain severity and functional status, with no difference found between gabapentin-experienced versus gabapentin-naïve patients.

Spinal neuromodulation as a novel surgical option for failed back surgery syndrome following rhBMP exuberant bony growth in instrumented lumbar fusion: A case report and literature review.

BACKGROUND: Bone morphogenic protein (BMP) for instrumented lumbar fusion was approved in 2002, and since then has led to an increasing incidence of BMP-related neuropathic pain. These patients are usually resistant to conventional medical therapy and frequently undergo multiple surgical revisions without any pain relief. CASE DESCRIPTION: A 58-year-old male was referred to the author's outpatient clinic after four lumbar surgeries did not provide satisfactory pain relief. During his 10 years of suffering from low back pain after an injury, the patient was resistant to conventional and interventional treatment options. He was experiencing severe back pain rated 10/10, as well as right lower extremity pain, numbness, tingling, and motor deficits. Outside spine specialists had performed revision surgeries for BMP-related exuberant bone formation at L5-S1, which included the removal of the ipsilateral hardware and debridement of intradiscal and intraforamina heterotrophic exuberant bony formation. The author implanted the patient with a permanent continuous spinal cord stimulator, after which he achieved complete pain relief (0/10) and restoration of motor, sensory, autonomic, and sphincter functions. CONCLUSION: This is the first reported case of restorative function with neuromodulation therapy in a BMP-induced postoperative complication, which is considered as a primarily inflammatory process, rather than nerve root compression due to exuberant bony formation. We hypothesize that neuromodulation may enhance blood flow and interfere with inflammatory processes, in addition to functioning by the accepted gate control theory mechanism. The neuromodulation therapy should be strongly considered as a therapeutic approach, even with confirmed BMP-induced postoperative radiculitis, rather than proposing multiple surgical revisions.

Are there a guidelines for implantable spinal cord stimulator therapy in patients using chronic anticoagulation therapy? - A review of decision-making in the high-risk patient.

BACKGROUND: Spinal cord stimulators (SCSs) are gaining increasing indications and utility in an expanding variety of clinical conditions. Complications and initial expenses have historically prevented the early use of SCS therapy despite ongoing efforts to educate and promote its utilization. At present, there exists no literature evidence of SCS implantation in a chronically anticoagulated patient, and neuromodulation manufacturers are conspicuously silent in providing warnings or recommendations in the face of anticoagulant use chronically. It would appear as through these issues demand scrutiny and industry as well as neuromodulation society advocacy and support in terms of the provision of coherent guidelines on how to proceed. CASE DESCRIPTION: A 79-year-old male returned to the neurosurgical clinic with persistent low back pain and leg heaviness due to adjacent level degenerative spondylosis and severe thoracic spinal stenosis. The patient had a notable history of multiple comorbidities along with atrial fibrillation requiring chronic anticoagulation. On initial presentation, he was educated with three choice of conservative medical therapy, intrathecal drug delivery system implantation, or additional lumbar decompression laminectomy with instrumented fusion of T10-L3 and a palliative surgical lead SCS implantation. DESCRIPTION: A 79-year-old male returned to the neurosurgical clinic with persistent low back pain and leg heaviness due to adjacent level degenerative spondylosis and severe thoracic spinal stenosis. The patient had a notable history of multiple comorbidities along with atrial fibrillation requiring chronic anticoagulation. On initial presentation, he was educated with three choice of conservative medical therapy, intrathecal drug delivery system implantation, or additional lumbar decompression laminectomy with instrumented fusion of T10-L3 and a palliative surgical lead SCS implantation. CONCLUSION: Our literature search did not reveal any evidence of SCS therapy among patients with chronic anticoagulation. This case illustrated a complicated clinical case scenario wherein a percutaneous SCS implantation would normally be contraindicated due to severe thoracic spinal stenosis and chronic anticoagulation which could lead to possible paralysis or even a lethal consequences associated with the possible formation of a thoracic epidural hematoma.

Pain and sex hormones: a review of current understanding.

Multiple epidemiologic studies have demonstrated an increased prevalence for women in several chronic pain disorders. Clinical and experimental investigations have consistently demonstrated sex-specific differences in pain sensitivity and pain threshold. Even though the underlying mechanisms responsible for these differences have not yet been elucidated, the logical possibility of gonadal hormone influence on nociceptive processing has garnered recent attention. In this review, we evaluated the complex literature regarding gonadal hormones and their influence on pain perception. We reviewed the numerous functions of gonadal hormones, discussed the influence of these hormones on several common chronic pain syndromes (migraine, tension and cluster headaches, fibromyalgia, temporomandibular syndrome, rheumatoid arthritis and back pain, among others), and have attempted to draw conclusions from the available data.

Should routine MRI of the lumbar spine be required prior to lumbar epidural steroid injection for sciatica pain?

BACKGROUND: We describe three patients who received lumbar epidural steroid injections (LESI) for lumbosacral radicular pain that resulted in worsening of their symptoms. The procedures were performed following a review of remote diagnostic imaging studies. These cases demonstrate the lack of consensus in pain management domains for how to approach the workup and treatment of persistent/chronic low back pain, with a noted fragmentation in pain management strategies and applied therapies. CASE DESCRIPTION: We present three patients; two female patients (37 and 38 years old) undergoing LESI for remotely diagnosed disc herniations, and one 61-year-old male receiving an LESI for a presumed, unverified lumbar intervertebral disc disorder. Following a worsening of symptoms after LESI, neurosurgical consultations ultimately determined the presence of, respectively, an epidural hematoma, a neurilemoma, and a lung cancer metastasis to the sacrum as the source of symptoms, instead of being due to the intervertebral disc pathology. CONCLUSIONS: We would like to emphasize several principles in the diagnosis and use of imaging of the lumbosacral region prior to undertaking invasive neuraxial procedures.

UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids.

Although the functional interaction between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) is essential in ubiquitin (Ub) signalling, the criteria that define an active E2-E3 pair are not well established. The human E2 UBCH7 (also known as UBE2L3) shows broad specificity for HECT-type E3s, but often fails to function with RING E3s in vitro despite forming specific complexes. Structural comparisons of inactive UBCH7-RING complexes with active UBCH5-RING complexes reveal no defining differences, highlighting a gap in our understanding of Ub transfer. Here we show that, unlike many E2s that transfer Ub with RINGs, UBCH7 lacks intrinsic, E3-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin (also known as PARK2) and human homologue of ariadne (HHARI; also known as ARIH1). Found in all eukaryotes, RBRs regulate processes such as translation and immune signalling. RBRs contain a canonical C3HC4-type RING, followed by two conserved Cys/His-rich Zn(2+)-binding domains, in-between-RING (IBR) and RING2 domains, which together define this E3 family. We show that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer Ub through an obligate thioester-linked Ub (denoted ∼Ub), requiring a conserved cysteine residue in RING2. Our results define the functional cadre of E3s for UBCH7, an E2 involved in cell proliferation and immune function, and indicate a novel mechanism for an entire class of E3s.

A UbcH5/ubiquitin noncovalent complex is required for processive BRCA1-directed ubiquitination.

Protein ubiquitination is a powerful regulatory modification that influences nearly every aspect of eukaryotic cell biology. The general pathway for ubiquitin (Ub) modification requires the sequential activities of a Ub-activating enzyme (E1), a Ub transfer enzyme (E2), and a Ub ligase (E3). The E2 must recognize both the E1 and a cognate E3 in addition to carrying activated Ub. These central functions are performed by a topologically conserved alpha/beta-fold core domain of approximately 150 residues shared by all E2s. However, as presented herein, the UbcH5 family of E2s can also bind Ub noncovalently on a surface well removed from the E2 active site. We present the solution structure of the UbcH5c/Ub noncovalent complex and demonstrate that this noncovalent interaction permits self-assembly of activated UbcH5c approximately Ub molecules. Self-assembly has profound consequences for the processive formation of polyubiquitin (poly-Ub) chains in ubiquitination reactions directed by the breast and ovarian cancer tumor susceptibility protein BRCA1.

A circularly permuted myoglobin possesses a folded structure and ligand binding similar to those of the wild-type protein but with a reduced thermodynamic stability.

A circular permutein of sperm whale myoglobin in which the G helix is C-terminal, the H helix is N-terminal, and 16 amino acids link the H helix to the A helix has been expressed in Escherichia coli. The permutein sequence begins with Gly121 (using the numbering scheme for the wild-type protein) and terminates with Pro120. The ligand binding function of the permutein was assayed using stopped-flow methods and shown to be essentially identical to that of the wild-type protein. In addition, one- and two-dimensional NMR studies of the cyanomet isoform of the permutein show a nativelike structure with a heme binding pocket very similar to that of the wild-type myoglobin. Although the structure and function of the permutein resemble those of the wild-type myoglobin, the permutein is less stable to chemical denaturation by 5.2 kcal/mol.