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Targeted Peripheral Nerve-directed Onabotulinumtoxin A Injection for Effective Long-term Therapy for Migraine Headache.

ABSTRACT: Onabotulinumtoxin A (BOTOX) is an FDA-approved treatment for chronic migraine headaches (MHs) that involves on-label, high-dose administration across 31 anatomic sites. Anatomically specific peripheral nerve trigger sites have been identified that contribute to MH pathogenesis and are amenable to both BOTOX injection and surgical decompression. These sites do not always correlate with the on-label FDA-approved injection pattern, but represent a more targeted approach. The efficacy of peripheral nerve-directed BOTOX injection as an independent long-term therapeutic option has not been investigated.The technique for peripheral nerve-directed therapeutic long-term BOTOX injection is described. A retrospective review was subsequently completed for 223 patients with MH. Sixty-six patients elected to proceed with diagnostic BOTOX injections. Of these, 24 continued long-term therapeutic BOTOX injections, whereas 42 matriculated to surgery. Outcomes were tracked.Initial outcomes included significant improvement in migraine headache index (MHI) (53.5?±?83.0, P < 0.006), headache days/mo (9.2?±?12.7, P < 0.0009), and migraine severity (2.6?±?2.5, P < 0.00008) versus baseline. MHI improved from the initiation of diagnostic injections to the establishment of steady-state injections (P < 0.002), and further improved over time (P < 0.05, mean follow-up 615 days) with no desensitization observed. Decompressive surgery resulted in significant improvement in MHI (100.8?±?109.7, P < 0.0000005), headache days/mo (10.8?±?12.7, P < 0.000002), migraine severity (3.0?±?3.8, P < 0.00001), and migraine duration in hours (16.8?±?21.6, P < 0.0007). MHI improvement with surgery was better than long-term BOTOX injections (P < 0.05).Though inferior to surgical decompression, preliminary data demonstrate that targeted peripheral nerve-directed BOTOX injection is an effective primary therapy for MH representing a possible alternative to nondirected BOTOX injection with decreased dosage requirements and potentially decreased cost.

SUBMITTER: Janis JE

PROVIDER: S-EPMC5404453 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Targeted Peripheral Nerve-directed Onabotulinumtoxin A Injection for Effective Long-term Therapy for Migraine Headache.

Janis Jeffrey E JE Barker Jenny C JC Palettas Marilly M

Plastic and reconstructive surgery. Global open 20170328 3

<h4>Background</h4>Onabotulinumtoxin A (BOTOX) is an FDA-approved treatment for chronic migraine headaches (MHs) that involves on-label, high-dose administration across 31 anatomic sites. Anatomically specific peripheral nerve trigger sites have been identified that contribute to MH pathogenesis and are amenable to both BOTOX injection and surgical decompression. These sites do not always correlate with the on-label FDA-approved injection pattern, but represent a more targeted approach. The effi ...[more]

PMID: 28458982

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Project description:BACKGROUND:Peripheral nerve injury in the upper extremity is linked to high socioeconomic burden, yet cost-analyses are rare and from small cohorts. The objective of this study was to determine the costs and long-term socioeconomic effects of peripheral nerve injuries in the upper extremity in Germany. METHODS:We analyzed data of 250 patients with 268 work-related upper extremity nerve injuries from acute treatment to long-term follow-up on rehabilitation, sick-leave and disability-pension. RESULTS:Patients were on average 39.9±14.2 years old, male (85%) and mean inpatient treatment was 7±6 days. Location of nerve was 8% (N = 19) proximal to the wrist, 26% (N = 65) at the wrist and metacarpus, and 66% (N = 166) at phalangeal level. Acute in-patient treatment for (single) median nerve injury accounted for 66% with hospital reimbursement of 3.570€, ulnar nerve injury for 24% and 2.650€ and radial nerve injury for 10% and 3.166€, all including finger nerve injuries. The remaining were combined nerve injuries, with significantly higher costs, especially if combined with tendon 5.086€ or vascular injury 4.886€. Based on location, nerve injuries proximal to the wrist averaged 5.360±6.429€, at the wrist and metacarpus 3.534±2.710€ and at the phalangeal level 3.418±3.330€. 16% required rehabilitation with average costs of 5.842€ and stay of 41±21 days. Sick leave was between 11-1109 days with an average of 147 days with socioeconomic costs of 197€/day, equaling on average 17.640€. 30% received a mean yearly disability pension of 3.187€, that would account to 102.167€ per lifetime. CONCLUSION:This large German patient sample indicates that nerve injury has a major impact on function and employment, resulting in significant health care costs. Both proximal and distal nerve injuries led to long-term disability, subsequent sick-leave and in 30% to permanent disability pension. These data are determined to support future studies and health economical work on prevention, treatment and rehabilitation of these often small injuries with great consequences.

Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3-6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817-29. ©2017 AACR.

Project description:BackgroundCurrently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of <24 hours. A liposomal bupivacaine formulation (EXPAREL, Pacira Pharmaceuticals, Inc., San Diego, CA), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration but not peripheral nerve blocks.MethodsBilateral single-injection femoral nerve blocks were administered in healthy volunteers (n = 14). For each block, liposomal bupivacaine (0-80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received 2 different doses, 1 on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally.ResultsThere were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04-0.14, P = 0.002) and tolerance to cutaneous current (-0.03 mA/mg, SE = 0.01, 95% CI, -0.04 to -0.02, P < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI, 43%-93%), block duration usually lasted much longer: for bupivacaine doses >40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%-100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%-100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, -0.27 to 0.39, P = 0.707).ConclusionsThe results of this investigation suggest that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of >24 hours for the highest doses examined. However, the high variability of block magnitude among subjects and inverse relationship of dose and response magnitude attests to the need for a phase 3 study with a far larger sample size, and that these results should be viewed as suggestive, requiring confirmation in a future trial.

Dataset Information

Targeted Peripheral Nerve-directed Onabotulinumtoxin A Injection for Effective Long-term Therapy for Migraine Headache.

Publications

Targeted Peripheral Nerve-directed Onabotulinumtoxin A Injection for Effective Long-term Therapy for Migraine Headache.

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